EMBRYO

Question 1

Development (maturation) of sperm

Answer 1

• Primordial germ cells
  
  • migrate from the yolk sac into developing gonads,
  • where they divide and differentiate into spermatogonia
• The primary sex cords:
  
  • At this stage, these cords are comprised of:
    
    • Primordial germ cells, pre-Sertoli cells, and a surrounding layer of myoid cells.
  • Later, primary sex cords differentiate into the seminiferous cords , which give rise to the
    
    • seminiferous tubules,​
    • straight tubules,
    • and rete testis
• Early in male development, mesenchyme separating the seminiferous cords gives rise to Leydig (interstitial) cells that produce testosterone
• Spermatogenesis=
  
  • Process by which spermatogonia develop into sperm
  • Duration 74 days
  • Begins shortly after puberty
  • Stages
    
    • 1- Spermatogonial phase
    • 2- Spermatocyte phase (meiosis)
    • 3- Spermatid phase (spermiogenesis)
    • Maturation phase→ mature spermatozoon

1- Spermatogonial phase

• Spermatogonial stem cells divide by mitosis to to provide a population of spermatogonia
• Classification of cells:
  
  • A dark/ A pale
    
    • Dark
      
      • Ovoid ncl, inensly basophillic
      • fine granular chromatin
      • stem cells of seminiferous spithelium
  • A Pale→ B
    
    • Ovoid ncl, pale stained
    • fine granular chromatin
    • produce sperm…
  • B
    
    • Spherical ncl, largly clumps of condensed chromatin alaong ncl envelope round central nucleolus
    • →Primary Spermatocyte
  • A diffenciates into B?

2- Spermatocyte phase (meiosis)

• Primary spermatocyte undergoes meiosis to reduce the chromosome number and amount of DNA
  
  • Before meiosis I
    
    • 2n chromosomes and 4d DNA
  • Meiosis I:
    
    • Product→ secondary spermatocyte:
      
      • Results in reduction to 1n and 2d (haploid)
        
        • Prophase I:
          
          • leptotene, zygotene, pachytene, diplotene and diakinesis
          • Lasts for 3 weeks
          • chromatin condenses into visable chromosomes
        • Metaphase I, anaphase I, telophase I, incomplete cytokinesis
          
          • Paired homologus chromosomes align (tetrads), and crossing over (in synaptonemal complexes), seperate
  • Meiosis II:
    
    • Product →spermatid: 1n, 1d (hapoloid)
    • Secondary spermatocytes enter prophase II w/o synthesysisng new DNA
      
      • Metaphase: sister chromatids line up
      • A: seperate

3- Spermatid phase (spermiogenesis)

• Extensive cell remodeling and diffrentiation into mature sperm
  
  • Golgi phase
    
    • Acrosomal vesicles
      
      • ​Granules rich in glycoproteins and mitochondria shifted to the periphery
      • Determining anterior pole of sperm
    • Centrioles
      
      • Migrate to the opposite pole of the nucleus (posterior pole), distal centriole starts to form the axoneme
        
        • initiated the assembly of 9 peripheral microtubule doublets and 2 central microtubules the consitiue the axoneme of the sperm tail
  • Cap phase
    
    • Acrosomal vesicle extends and stretches over the anterior part of the nucleus
  • Acrosomal phase
    
    • Spermatid is turning and is deeply inserted into the Sertoli cell cytoplasm.
    • Development of the the tail, condensation and elongation of the nucleus.
      
      • Developing flagellum extends into the lumen of the seminiferous tubule
    • Microtubule manchette
      
      • Organisation of cytoplamsic mictotubules into a cylidrical sheath which extends from the posterior rim of the acrosome twards the posterior pole
    • Cytoplasm is pulled back
    • Mitochondria form a sheath in the middle piece.

4- Maturation phase→ mature spermatozoon

• Advancing chromatin condensation
• Phagocytosis of exsess cytoplasm by Sertoli cells (AKA residual body)
• Release of spermatozoa into the lumen of the seminiferous tubule (AKA: spermination)
• Disconnections of intercellular bridges.

Newly released sperm cells are processed in the epididymis where they aquire motility and undergo further maturation

• Carried by fluid secreted from the sertoli cells
• Though the seminiferous tubules, facillitated by peristaltic contractions
  
  • of peritubular contractile cells of the lamina proptia
• Enter straight tubules
• At mediastinum the fluid and sperm enter the rete testies: simple cuboidal epithelium
• Move into the extracellular portion of the efferent ductules
  
  • first part of the excurrent duct system
• And then to the proximal protion of the duct of epididymis
• As they move through the highly colied duct they aquire motility and undergo several maturation stages
  
  • Condensation of DNA, head of sperm decreases in size
  • Further reduction of cytoplasm- cells becomes more slender
  • Changes in plasma membrane lipids, protiens and glycosylation
  • Alteration in the outer acrosomal membrane (decapitation)
• duct of epididymis

Mature sperm:

• Head -
  
  • the mass of the largest part of sperm, contains a nucleus with haploid genetic equipment (n) and cytoplasm.
  • In front of the head is a sac called an acrosome , which was formed during spermatogenesis by fusing the follicles of the Golgi apparatus .
    
    • It acts as a lysosome and serves to disrupt the structures surrounding the oocyte (corona radiata and zona pellucida).
    • It contains several hydrolytic enzymes such as hyaluronidase (it breaks down glycosaminoglycans), acrosin (protease), neuraminidase and acid phosphatase .
• Neck - a structure connecting the head and the whip.
• Tail - the part of the sperm that allows it to move. It contains a bundle of microtubules anchored in the basal body. It consists of three segments:
  
  • Connecting (middle) segment - contains a number of mitochondria providing energy for movement.
  • Main segment .
  • End part .

The size of the sperm is about 60 μm, of which only 5 μm falls on the head, the rest is the flagellum.

Question 2

Development (maturation) of oocyte

Answer 2

Follicular development : ALSO IN FEMALE REPRODUCTIVE SYSTEM, “OVARY”

*****יותר מעודכן שם

1- Primordial follicles

• Earliest stage of development
• First appear in the 3rd month of development
• Independent of gonadotropin stimulation
• Found in stroma of cortex, just beneath tunica albuginea
• Follicle structure:
  
  • single layer of squamous follicle cells surrounds oocyte
  • Ouer surface: basal lamina
• Oocyte structure:
  • (30 μm)
  • Large nucleus with well visible nucleolus,
  • Balbiani body: accumilation of mitochondria, Golgi complex, GER and SER, lysosomes
  • Annulate lamellae????

2- Growing follicles= Primary

• Unilaminar primary follicle -
  
  • Oocyte Structure
    
    • 150 μm: oocyte enlarges
  • Follicle structure:
    
    • Simple layer of cuboidal follicular cells (when cells become cuboidal, follice is diffiened as primary)
    • • Beggins secreting zona pellucida around the oocyte (glycoprotien layer)
        
        • composed of 3 classes of sulfated acidic ZP glycoprotiens: ZP1, ZP2, ZP3 (inducer of acrosome reaction)
• Multilaminar primary follicle
  
  • Primary ocyte
  • Zona pellucida
    
    • acellular envelope
    • contains hglycoprotiens produced by gransulosa cells (essential for penetration of a sperm cell into oocyte)
  • Follicle structure: ​
    
    • Single layer of follicular cells give rise to stratified epithlium: Granulosa cells
      
      • proliferation is mediated by TGF- beta (transforming growth factor)
    • Basal lamina remains the outer most layer
    • Gap junctions develop between granulosal cells
    • Granulosa cells adjacent to the zona pellucida are columnar and form a layer called corona radiata
    • Granulosa cells proliferate: stromal cells
      
      • cells immediatly surrounding the follicle, form a sheath of CT cells, theca folliculi, just external to the basal lamina
• Maturation of oocyte occurs in the primary follcile
  
  • golgi elements develop from balbiani bodies
  • cells organells increase
  • speciflized cortical granules beneth oolemma (plasma membrane)
  • numerous irregular microvilli project into preivitelline space between oocyte and granulosa cells
• From growing follicle to vesicular follicle:
  
  • FSH dependent
  • other growth factors
  • calcium ions
• Vesicular follcile/ seconday preantral follcile
  
  • Zona pellucida: growing thickness, becomes more pronounced
  • Granulosa: 6-12 layers, merging cavities filled with follicular fluid
    
    • until forming a single space: antrum
  • Basment membrane
  • Theca
    
    • inner theca: with thecal endocrine cells, fibroblasts and sense collagen fibers
      
      • thecal endocrine cells: carry receptors for LH, which stimulate andorgen production
    • outer theca: fibroblasts, smoothe muscles cells and collagen network
  • Cumulus oophorus

3- Mature/ graafian follicles

• (> 20 mm)
• Spaces grow
• Cummulus oophorus of granulosa cells carrying oocyte with zona pellucida protrudes into antrum,
  
  • a layer of granulosa cells around the oocyte forms corona radiata,
• The the cumulus cells are gradually released from the other granulosa cells in prepiration for ovulation
  
  • Thecal cells become more prominent, theca folliculi interna is richly vascularized.
    
    • LH stimulates theca interna to decrete andorgens (estrogen precusors)
    • some androgen are transported to the sER in granulosa cells
    • in response to FSH, granulosal cells turn the andorgens into estrogen: which in turn stimulate the granulosal cells to priliferate and increase the size of the follcile

OOGENESIS, GERM CELL DEVELOPMENT

Female germ cells - eggs - develop in the ovaries.

• The human egg has a diameter of 0.1 mm,
  
  • The size is species specific.
• The egg is formed from germ line cells in the ovarian cortex.
• About 2 million germ cells - oogonia - are established in the ovary
  
  • An egg, like any gamete, contains half the number of chromosomes (22 somatic + 1 sex).

The multiplication of oogonia by mitotic division

• Begins at the end of the 2nd month and ends in the 5th month of intrauterine development in the first phase of reproductive division ( meiosis ).
• Cells of coelomic epithelium are attached to oogonia in one layer, so-called primordial follicles are formed
• From oogonia,
  
  • mitoses give rise to first-order oocytes
    
    • (in women, their formation - the growth stage - ends as early as the 3rd month after birth).
  • First-order oocytes enter meiosis.
    
    • The prophase of the first meiotic division takes place until the diploten stage,
    • In which the oocytes remain until the hormonal initiation of further maturation, the so-called dictyotenic stage.
• The maturation of individual follicles then continues only after puberty due to hormones.
  
  • In some species, the stimulus for the continuation of the first maturation division is progesterone,
  • in others the change in estrogen and progesterone levels during the cycle.
  • The ripening stage takes place throughout the generation period (for a woman in cycles of Ø 28 days - it always matures after one egg).
    
    • During a woman’s lifetime, 300-400 eggs are released from the ovary, but only about 400-500 eggs mature .

The first meiotic division (in metaphase) results in two haploid cells from the developing oocyte:

• one oocyte II. order
• one rudimentary cell - the so-called polocyte (pole body).

The cell remains undivided.

• The second meiotic division is initiated after ovulation
  
  • And is completed only after the penetration of sperm into the egg, when from oocyte II. order, one egg and the other pole body are formed .
  • At the same time, the 1st pole cell still undergoes mitosis, it is divided into two and all 3 pole bodies soon disappear and are resorbed.
  • During egg maturation before ovulation, some of the egg’s genes are strongly expressed. Synthesis of RNA , proteins and various storage substances, some mRNAthey are transported to the cytoplasm, where they are stored in an inactive form and activated only after fertilization of the egg. Other storage substances, proteins and RNA of all types are transported into the egg from the follicle cells. Some storage substances are synthesized in the mother’s liver and transported by the blood to the egg. The structure of the egg and the amount of substances are thus significantly affected by the genes of the maternal somatic cells. In disorders of hormonal regulation, the proliferative phase of the cycle is termed, referred to as “egg maturation”. The result is a disintegration of the cell structure as well as a disorder of the dividing spindle and the formation of nondisjunctions of chromosomes and aneuploidy of the fetus .
• • *

Question 3

Fertilization and early development of the human embryo

Answer 3

Fertilization:

• Process by which male and female gametes fuse
• Mostly occurs in the ampullary region of the uterine tube.
• Spermatozoa may remain viable in the female reproductive tract for several days.
• Only 1% of sperm deposited in the vagina enter the cervix.
• Movement of sperm from the cervix to the oviduct (minimum of 2 to 7 hours):
  
  • primarily by sperm own propulsion
  • movements of fluids created by uterine cilia.
• At ovulation, sperm become motile and swim to the ampula
  
  • Possibly because of chemo-attractants produced by cumulus cells surrounding the egg.
• Spermatozoa are not able to fertilize the oocyte before they undergo:
  
  • Capacitation - approximately 7 hours
    
    • Acrosome region loses a glycoprotein coat and seminal plasma
    • This process is due to sperm interaction with mucosal surface of the tube.
    • Only capacitated sperm can pass through the corona cells and undergo the acrosome reaction
  • Acrosome reaction - occurs after binding to the zona pellucida
    
    • This reaction is release of enzymes needed to penetrate the zona pellucida, including acrosin and trypsin-like substances.
    • The reaction destroys the plasma membrane at the acrosome region

Phases of fertilization

Phase 1 - Penetration of the corona radiata

• Only 300 to 500 sperm reach the site of fertilization.
• It is thought that the others aid the one fertilizing sperm in penetrating the barriers protecting the female gamete.
• Capacitated sperm pass freely through corona cells.

Phase 2 - penetration of the zona pellucida

• The zona is a glycoprotein shell surrounding the egg, and in charge of sperm binding and starting the acrosome reaction.
  
  • Both binding and the acrosome reaction are mediated by the ligand ZP3.
• Release of acrosomal enzymes (acrosin) allows sperm to penetrate the zona, and come in contact with the plasma membrane of the oocyte surface.
• Zona reaction: the permeability of the zona pellucida changes when the head of the sperm comes in contact with the oocyte surface
  
  • In order to prevent any more sperm from entering the egg
  • In activation of species-specific receptor sites for spermatozoa on the zona surface: a result of release of lysosomal enzymes from granules of the plasma membrane of the oocyte.

Phase 3 - fusion of oocyte and sperm cell membranes 

• The initial adhesion of sperm to the oocyte caused by the interaction of integrins on the oocyte and their ligands, disintegrins, on sperm.
• After adhesion, the plasma membranes of the sperm and egg fuse.
• Fusion is between the oocyte membrane and the membrane that covers the posterior region of the sperm head. (head’s membrane was destroyed during acrosome reaction)
• Both the head and tail of the spermatozoon enter the cytoplasm of the oocyte, but the plasma membrane is left behind on the oocyte surface.

Response to sperm penetration:

• Cortical and Zona reactions
  
  • Release of cortical oocyte granules, which contain lysosomal enzymes. Causes -
    
    • The oocyte membrane becomes impenetrable to other spermatozoa
    • The zona pellucida alters its structure and composition to prevent further sperm binding and penetration.
  • These reactions prevent polyspermy (penetration of more than one).
• Resumption of the second meiotic division -
  
  • The oocyte finishes its second meiotic division immediately after entry of the spermatozoon.
  • Creating the second polar body; and the definitive oocyte.
  • Chromosomes arrange themselves in a vesicular nucleus known as the female pronucleus
• Metabolic activation of the egg
  
  • Activating factor is carried by the spermatozoon. Post fusion activation may be the initial of embryogenesis.
• The spermatozoon moves until it lies close to the female pronucleus.
• Its nucleus becomes swollen and forms the male pronucleus (the tail detaches and degenerates).
• The 23 maternal and 23 paternal (double) chromosomes split longitudinally at the centromere, and sister chromatids move to opposite poles, providing each cell of the zygote with the normal diploid number of chromosomes and DNA.

Main results of fertilization:

• restoration of the diploid number of chromosomes
• Determination of the sex of the new individual
• Initiation of cleavlage

Question 4

Development and implantation of the blastocyst

II

Answer 4

Cleavage

• Once the zygote has reached the two-cell stage, it undergoes a series of mitotic divisions, increasing the numbers of cells.
  
  • These cells, which become smaller with each cleavage division, are known as blastomeres.
  • 30 hrs: 2 cells
  • 40 hrs: 4 cells
  • 4 days: 16 cells: morula
• From 8+ cells:
  
  • Blastomeres forms a compact ball with tight junctions.

Blastocyst Formation

• Morula enters the uterine cavity: 4th day→
• Fluid begins to penetrate through the zona pellucida into the intercellular spaces of the inner cell mass, forming:
• Blastocele cavity: A combined space created by connection intercellular spaces, due to fluids penetration.
• Blastocyst - an embryo after blastocele appears.
  
  • The inner cell mass -
    
    • Gives rise to tissues embryo proper and will be later called embryoblast.
  • The outer cell mass
    
    • forms the trophoblast, becomes flat and form the epithelial wall of the blastocyst (which later contributes to the placenta.) ​
    • ​Abembryonic pole and Embryonic pole

Implantation

Basic condition to initiate implantation process:

• Dissolution of the zona pelucida
  
  • Trypsin-like enzyme is secreted by few cells of trophoblast. The blastocyst “hatches” from the zona by digesting a hole.

Stages of implantation

• Apposition
• Adhesion
• Embedding in the endometrium.

Day 6 Apposition:

• The very first loose, connection between the blastocyst and the endometrium is called the apposition
• Apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass
  
  • the inner cell mass rotates inside the trophoblast to align to the apposition
• It involve integrins, expressed by the trophoblast, and the extracellular matrix molecules laminin and fibronectin.
  
  • Integrin receptors for laminin promote attachment, while those for fibronectin stimulate migration

Adhesion is a much stronger attachment to the endometrium than the loose apposition.

• The adhesion can occur when beforehand the uterus has entered its secretory phase (luteinizing phase). This reception-ready phase of the endometrium lasts 4 days (20th -23rd day) and is usually termed the “implantation window”

Day 7-8: Adhesion

• Blastocyst is partially embedded in the endometrial stroma.
• The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.
• Trophoblast is differentiated into two layers, at the embryonic pole of the blastocyst:
  
  • cytotrophoblast
    
    • ​inner layer
    • mononucleaed cells
    • produce primary chorionic villi
  • syncytiotrophoblast
    
    • outer layer
    • mutli nucleaed

Embedding in the endometrium.

Syncytiotrophoblast forms a syncytium:

• A multi-nucleic layer without cell boundries
  
  • Produces lytic enzymes and secretes factors that cause apoptosis of the endometrial epithelial cells.
• With the implantation of the blastocyst in the endometrium the syncytiotrophoblast develops quickly and will entirely surround the embryo as soon as it has completely embedded itself in the endometrium.
• The uterine mucosa reacts to the implantation by the decidual reaction.
  
  • Decidual reaction: set of changes in the endometrium of the uterus that prepare it for implantation of an embryo.
  • Swelling of endometrial cells, due to high amounts of glycogen and other nutrients for the embryo.
  • Helps the embryo survive until more stable nutrition method is established.
    
    • The syncytiotrophoblast cells phagocytize the apoptotic decidual cells of the endometrium and resorb the proteins, sugars and lipids that have been formed there.
    • They also erode the canals of the endometrial glands and the capillaries of the stroma.
• In the middle of the 2nd week extracellular vacuoles appear in the ST.
  
  • They join together forming lacunae.
  • Initially these lacunae are filled with tissue fluids and uterine secretions.
  • Following the erosion of the maternal capillaries, their blood fills the lacunae that later develop further into intervillous spaces.
  • The invasive growth of the ST ceases in the zona compacta of the endometrium.
  • At around the 13th day the primitive utero-placental circulatory system arises.
• Complete implantation of the embryo into the endometrium and covering of the implantation location by a fibrin plug.

Uterus at Time of Implantation - the wall of the uterus consists of three layers.

• Endometrium or mucosa lining the inside wall
  
  • Compact
  • Spongy
  • Basal (constant)
• Myometrium, a thick layer of smooth muscle;
• Perimetrium, the peritoneal covering lining the outside wall

Cyclic changes of endometrium (28 days under hormonal control by ovaries), three stages -

• Proliferative phase -
  
  • Begins at the end of the menstrual phase.
  • Under the influence of estrogen, and parallels growth of the ovarian follicles.
• Secretory phase -
  
  • Begins approximately 2 to 3 days after ovulation in response to progesterone produced by the corpus luteum.
• Menstrual phase -
  
  • If fertilization does not occur, shedding of the endometrium (compact and spongy layers) marks the beginning of the menstrual phase.
  • If fertilization does occur, the endometrium assists in implantation and contributes to formation of the placenta.

If the oocyte is not fertilized, venules and sinusoidal spaces gradually become packed with blood cells, and an extensive diapedesis of blood into the tissue is seen.

When the menstrual phase begins, blood escapes from superficial arteries, and small pieces of stroma and glands break away.

During the following 3 or 4 days, the compact and spongy layers are, and the basal layer is saved.

The basal layer, which is supplied by its own arteries, the basal arteries, functions as the regenerative layer in the rebuilding of glands and arteries in the proliferative phase.

Question 5

Anomalies of implantation, ectopic pregnancy

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Answer 5

• Normal fertilization always takes place outside the uterus in the outer third, ampulla, of the uterine tube.
• The fertilized oocyte migrates through the tube to the uterus.
• The implantation takes place on the 6th day in the uterine endometrium, most commonly into the anterior or posterior wall of the uterus)
• If migration is delayed for whatever reason, the blastocyst can implant itself somewhere along the way to the uterus.
• Additional disturbances:
  
  • A delayed capture of the oocyte by the infundibulum
  • A disturbance of the peristalsis in the tube

Ectopic pregnancy

• Occurs when an embryo attaches outside of the uterus, most commonly in the fallopian tubes.
• Localization:
  
  • Fallopian tube (96% of cases):
  • Ovary (3% of cases)
  • Abdomen (1% of cases)
  • Cervix (very rare)

It can lead to hemorrhages and thus to sterility – due to rapture of the fallopian tube.

There are a total of 6 potential risk factors -

• Infections (fallopian tube infection, salpingitis)
• Surgical interventions in the pelvis
• Tobacco using
• In-vitro fertilization (IVF)
• Congenital anomalies (tube malformations)
• Endometriosis – ectopic fragments of the uterine mucosa

Question 6

Development of the Amniotic and Yolk Sacs, Chorion

Answer 6

Second week of development

Day 8:

• At the eighth day of development, the blastocyst is partially embedded in the endometrial stroma.
• Trophoblast has differentiated into two layers:
  
  • cytotrophoblast- inner layer of mononucleated cells
  • syncytiotrophoblast- outer multinucleated zone without distinct cell boundaries.
• Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc:
  
  • FGF: fibroblast growth factor
    
    • Hypoblast layer -
      
      • a layer of small cuboidal cells adjacent to the blastocyst cavity.
    • Epiblast layer -
      
      • a layer of high columnar cells adjacent to the amniotic cavity.
  • Amniotic cavity - a cavity that appears within the epiblast.
    
    • Development of the amniotic cavity : inter-cellular spaces between some cells of the embryoblast enlarge and fuse into cavity (this process is associated also with the apoptosis of single cells).
  • Amnioblasts - Epiblast cells adjacent to the cytotrophoblast.
• The endometrial stroma adjacent to the implantation site is edematous and highly vascular.
  
  • The large, tortuous glands secrete abundant glycogen and mucus.
  • The uterine glands synthesize or transport and secrete substances essential for survival and development of the embryo or fetus and associated extraembryonic membranes.

Day 9

• Surface epithelium at place of implantation is closed by a fibrin coagulum.
• Trophoblast development
  
  • At embryonic pole: vacuoles appear in the syncytium.
  • Lacunar stage: fusion of vacules to form large lacuna
• Embryoblast development
  
  • Exocoelomic (Heuser’s) membrane - flattened cells originating from the hypoblast form a thin membrane that lines the inner surface of the cytotrophoblast.
  • This membrane, together with the hypoblast, forms the lining of the exocoelomic cavity, or primitive yolk sac.

Days 11 and 12

• Blastocyst is completely embedded in the endometrial stroma, and the surface epithelium almost entirely covers the original defect in the uterine wall.
• Trophoblast development
  
  • lacunar spaces evident at the embryonic pole
  • Cells of the syncytiotrophoblast penetrate deeper into the stroma.
  • The lacunae become continuous with the sinusoids (Maternal capillaries, which are contacted and dilated) and maternal blood enters the lacunar system.
  • Uteroplacental circulation -
    
    • As the trophoblast continues to erode more and more sinusoids, maternal blood begins to flow through the trophoblastic system, establishing the uteroplacental circulation.
• Embryoblast development
  
  • ​Extraembryonic mesoderm-
    
    • Derived from yolk sac cells, appears between the inner surface of the cytotrophoblast and the outer surface of the exocoelomic cavity.
      
      • Loose connective tissue.
    • This tissue fills all of the space between the trophoblast externally and the amnion and exocoelomic membrane internally.
  • Large cavities develop in the extraembryonic mesoderm, and when these become confluent, they form a new space known as the extraembryonic coelom, or chorionic cavity.
    
    • This space surrounds the primitive yolk sac and amniotic cavity except where the germ disc is connected to the trophoblast by the connecting stalk.
    • Extraembryonic somatic mesoderm- line’s the cytotrophoblast and amnion. (outer)
    • Extraembryonic splanchnic mesoderm- the lining covering the yolk sac
• Bilaminar blastocyst or Bilaminar disc -the epiblast and the hypoblast, evolved from the embryoblast.
  
  • These two layers are sandwiched between two balloons:
    
    • The primitive yolk sac
    • The amniotic cavity.

Day 13

• Occasionally, bleeding occurs at the implantation site as a result of increased blood flow into the lacunar spaces.
  
  • Because this bleeding occurs near the 28th day of the menstrual cycle, it may be confused with normal menstrual bleeding and, therefore, cause inaccuracy in determining the expected delivery date.
• Trophoblast development:
  
  • Is characterized by villous structures.
  • Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by syncytium.
  • Primary villi - Cellular columns of cytotrophoblast with the syncytial covering.
• Embryoblast development
  
  • Formation of the extraembryonic coelom and its enlargement lead to reduction of the cavity of the primary yolk sac (forming the secondary yolk sac).
  • Endodermal cells (yellow) proliferate along the inner surface of exocoelomic membrane and form the wall of the secondary YS. Remnants of the exocoelomic cavity persist as exocoelomic cysts
    • = secondary yolk sac or definitive yolk sac.
      
      • This yolk sac is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• During its formation, large portions of the exocoelomic cavity are pinched off. These portions are represented by exocoelomic cysts, which are often found in the extraembryonic coelom or chorionic cavity.
• Meanwhile, the extraembryonic coelom expands and forms a large cavity, the chorionic cavity.
• The extraembryonic mesoderm lining the inside of the cytotrophoblast is then known as the chorionic plate.
• The only place where extraembryonic mesoderm traverses across the chorionic cavity is in the connecting stalk.
• With development of blood vessels, the stalk becomes the umbilical cord. –

Question 7

Formation of the fetal membranes

Basiclly same question as:

Development of the amniotic and yolk sacs, chorion

Answer 7

FORMATION OF FETAL MEMBRANES

Formation of the fetal membranes:

• Also known as extraembryonic membranes
  
  • (i.e., amnion, chorion, yolk sac, and allantois)

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Overview and opening

Prenatal perod: intrauterine development after fertilization of the ovum by sperm up until delivery

• Fertilization (→Zygote)
• Blastogenesis: first 2 weeks after fertilization
• Embryonic period: until end of 8th week (basis of organs are formed)
• Fetal period: until childbirth (growth and functional maturation of organs)

Week 1 of development:

• Ferrtilization→ Zygote→ Cleavlage (repeated mitotic division)→Blastomere (daugter cell of zygote) →Morula (16 cells)→ Blastocyst (inner and outer mass, cavity)→
  
  • Inner cell mass→ embryo proper: embryoblast
  • Outer cell mass→ trophoblast(which later contributes to the placenta.) ​
• Implantation beggins around day 6

Week 2 of development:

• Blastocyst is partially embedded in the endometrial stroma.
• Trophoblast differentiated into two layers:
  
  • Cytotrophoblast- inner layer of mononucleated cells
    
    • Will produce the primary chorionic villi, by protruding into syncytiotrophoblast
  • Syncytiotrophoblast- outer multinucleated zone without distinct cell boundaries.
    
    • The ​periphery the syncytiotrophoblast forms a syncytium
    • multi-nucleic layer without cell boundaries that arises from the fusion of cytotrophoblast cells
  • Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc
    
    • ​Hypoblast and epiblast
    • Two layers are sandwiched between cavities
      
      • Blastocyst cavity→ The primitive yolk sac
      • The amniotic cavity
        
        • Is hollowed out from the middle of the inner cell mass (epiblast part of embryoblast)
        • Amnioblasts: epiblast cells adjacent to the cytotrophoblast
• ​Day 9:
• Surface epithelium at place of implantation is closed by a fibrin coagulum.
• Lacunar stage:
  
  • Vacuoles appear in the syncytium→ fusion of vacules to form large lacuna

​****************************************

Formation of the fetal membranes: extraembryonic membranes

amnion, chorion, yolk sac, and allantois

• Formation of the Amnionic cavity
  
  • Bilaminar disc: Hypoblast and epiblast
  • Space between cytotrophoblast and epiblast is hollowed out
    
    • Amnioblasts: epiblast cells adjacent to the cytotrophoblast
• Formation of the yolk sac and chorion
  
  • Primative yolk sac
    
    • Proliferation of hypoblast cells→ extend around the blastocyst cavity→ forming the exocoelomic membrane, or Heuser’s membrane: Primative yolk sac
  • Definative yolk sac (secondary) and chorion
    
    • Formation of extraembryonic mesoderm (derived from yolk sac cells) appears between:
      
      • The inner surface of the cytotrophoblast
      • The outer surface of the exocoelomic cavity.
        
        • Loose connective tissue.
    • Large cavities develop in the extraembryonic mesoderm→ causing the mesoderm to split and displacment of primary yolk sac→
      
      • (Outer) extraembryonic somatic mesoderm:
        
        • Lines the cytotrophoblast and amnion
      • (Inner) extraembryonic splanchnic mesoderm:
        
        • The lining covering the yolk sac
    • A new space—the extraembryonic coelom, or chorionic cavity—forms by splitting of the extraembryonic mesoderm into two layers.
      
      • This cavity separates the embryo with its attached amnion and yolk sac from the outer wall of the blastocyst
      • Seperation occurs everywhere except the connecting stalk
    • Formation of the chorionic cavity and its enlargement lead to reduction of the cavity of the primary yolk sac:
      
      • A second wave of migration of hypoblast cells produces a new membrane that migrates out over the inside of the extraembryonic mesoderm (splanchnic) pushing the primary yolk sac in front of it.
        
        • This new layer becomes the endodermal lining of the secondary (definitive) yolk sac.
      • Chorionic cavity continues to enlarge
        
        • Remnants of the primary yold sac persist as exocoelomic cysts
      • The secondary yolk sac or definitive yolk sac: is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• Summary:
  
  • Definative yolk sac:
    
    • Extraembryonic endoderm
    • (Inner) extraembryonic splanchnic mesoderm
  • ​Connecting stalk: ???
    
    • ​​extraembryonic splanchnic mesoderm
  • Amnionic cavity
    
    • Amnioblasts and embryonic disc​
  • Chorionic plate
    
    • Extraembrionic somatic mesoderm,
    • Extraembryonic ectoderm
      
      • Cytotrophoblast
      • Syncytiotrophoblast
• The definitive yolk sac
  
  • Remains a major structure associated with the developing embryo through the 4th week and performs important early functions.
    
    • Extraembryonic mesoderm forming the outer layer of the yolk sac is a major site of hematopoiesis- blood formation
    • primordial germ cells can first be identified in humans in the wall of the yolk sac.
  • After the 4th week, the yolk sac is rapidly overgrown by the developing embryonic disc.
    
    • The yolk sac normally disappears before birth, but on rare occasions it persists in the form of a digestive tract anomaly called Meckel’s diverticulum

****************

Question 8

Embryonic disc and its differentiation

Formation of the germ layers

serratonin: nodal cascade, determines left side

Answer 8

End of week 2: overview

During implantation of the blastocyst, formation of:

• An embryonic disc from 2 layers of cells :
  
  • Hypoblast and epiblast cells
• The blastocyst is inside the endometrium
  
  • Operculum is covered by the epithelial tissue and connective tissue
• Formation of the chorionic cavity, secondary yolk sac
• Outer fetal membrane – is chorion
• Inner fetal membrane – is amnion
• Syncytiotrophoblast – is producing the human chorionic gonadotropin ( HcG )– into the maternal blood – to the kidneys – into the urine

Third Week of Development

Gastrulation: is a phase during which the single-layered blastula is reorganized into a trilaminar (“three-layered”) structure known as the gastrula.

• Bilaminar disc: (epithlial tissue)
  
  • epiblast: single layer of high columnar cells
  • hypoblat: single layer cubpidal cells
• Development of all three germ layers (ectoderm, mesoderm, and endoderm)
• All germ layers are derived from the epiblast !
• Formation of axsis:
  
  • cranio-caudal axis
  • ventro-dorsal axis
  • medial-lateral axis

General process:

• Begins with formation of the primitive streak on the surface of the epiblast.
  
  • Day 15-16: clearly visible as a narrow groove with slightly bulging regions on either side.
• Primitive node: at the cephalic end of the streak, a slightly elevated area surrounding the small primitive pit.
• Migration of the epiblast cells to the primitive streak and primitive node
  
  • Epithelio-mesenchymal transformation
    
    • Regulated by FGF 8 (fibroblast growth factor)
    • FGF-8 causes reduction of e cadherin molecules in the cells so there adherence junctions will be weak so they can migrate
• Invagination of the cells under the epiblast:
  
  • Migrate bilaterally and then cranially and laterally between endoderm and epiblast to form intraembryonic mesoderm
  • Some of these cells invade hypoblast, displacing the original hypoblast cells and replacing them with a layer of definitive endoderm.
  • Form notochordal process
  • After finishing of the cell migration the epiblast becomes ECTODERM

Migration of cells

• Mesoderm is missing where epiblasts and hypoblasts are tightlly apposed to each other
  
  • Oropharyngeal membrane
  • Cloacal membrane
• Cells from primative node/pit
  
  • 1st wave: will give rise to the prechordal plate
    
    • (prechordal plate - is a thickened of the endoderm that is in contact with ectoderm)
    • ​between the end of the notochordal processes and OM) is composed of the first cell population migrated from primative node. induction role in formbrain development
  • 2cd wave: notochordal process (precusor), prenotochordal cells
• Cardiogenic mesoderm?
• Primordial germ cells: migrate from caudal paet to(gonocytes)???
• most anteriorly:m lateral plate mesoderms: cardiogenic mesoderm
• Caudal parts: miagrate more lateral
• cranial parts: more to midline
• most anterior

Question 9

Development of the ectoderm and its differentiation

Development of the endoderm and its differentiation

Answer 9

Short review:

Gastrulation is the process in which the three germ layers (ectoderm, mesoderm and endoderm) are formed by successive waves of epiblast cells migrating through the primitive streak. Formation of the primitive streak on 15th day marks the first event of gastrulation. Cells from the epiblast migrate into the interior of the embryo, via the primitive streak, in a process termed invagination, which involves a cellular epithelial-to-mesenchymal transition (EMT). The initial wave of migrating cells (day 16) streams through the primitive streak, displacing the hypoblast cells to become definitive endoderm, which ultimately produces the future gut derivatives and gut linings.

In general terms, the ectodermal germ layer gives rise to organs and structures

Ectoderm:

• Epidermis and skin appandages
• In addition, it gives rise to subcutaneous glands, the mammary glands, the pituitary gland, and enamel of the teeth.

Neuroectoderm:

• that maintain contact with the outside world:
• the central nervous system
• the peripheral nervous system
• the sensory epithelium of the ear, nose, and eye.
• the epidermis, including the hair and nails.

Endoderm:

• Intraembryonic
• Extraembryonic

The Endoderm: the endoderm produces the gut tube and its derived organs, including:

The cecum, intestine, stomach, liver, pancreas, as well as thymus, lungs, thyroid and prostate.

This germ layer covers the ventral surface of the embryo and forms the roof of the yolk sac.

With development and growth of the brain vesicles, the embryonic disc begins to bulge into the amniotic cavity and to fold cephalocaudally. As a result of this folding, a continuously larger portion of the endoderm-lined cavity is incorporated into the body of the embryo proper.

In the anterior part, the endoderm forms the foregut; in the tail region, it forms the hindgut.

The part between foregut and hindgut is the midgut, which temporarily communicates with the yolk sac by way of broad stalk – the vitelline duct[yo1] .

At its cephalic end, the foregut is temporarily bounded by an ectodermal-endodermal membrane called the buccopharyngeal membrane (=oropharyngeal membrane).

In the fourth week, the membrane ruptures, establishing an open connection between the amniotic cavity and the primitivegut.

The hindgut also terminates temporarily at an ectodermal-endodermal membrane – the cloacal membrane, which breaks down in the 7th week to create the opening for the anus.

The endodermal germ layer initially forms the epithelial lining of the primitive gut and the intraembryonic portions of the allantois and vitelline duct.

During further development, it gives rise to:

Epithelial lining of the respiratory tract.

Parenchyma of the thyroid, parathyroid glands, liver and pancreas.

Reticular stroma of the tonsils and thymus.

Epithelial lining of the urinary bladder and urethra.

Epithelial lining of the tympanic cavity and auditory tube.

[yo1]Meckel’s Diverticulum.

Question 10

Development of the axial structures (notogenesis)

Development of the notochord and its significance for development of other structures

Development of the notochord and its significance for development of other structures

Stages of Notogenesis:

Pre-notochordal cells invaginated in the primitive pit, where they become intercalated in the hypoblast so that for a short time, the midline of the embryo consists of two cell layers that form the notochordal plate.

As the hypoblast is replaced by endoderm cells moving in at the streak, cells of the notochordal plate proliferateand detach from the endoderm:

On the ventral aspect of the neural groove an axial thickening of the endoderm takes place. This thickening appears as a furrow (the chordal furrow) the margins of which anastomose (come into contact), and so convert it into a solid rod of polygonal-shaped cells (the notochord) which is then separated from the endoderm.

They then form a solid cord of cells – the definitive notochord, which underlies the neural tube and serves as the basis for the axial skeleton.

The notochordal process grows cranially between the ectoderm and endo­derm until it reaches the prechordal plate, a small, circular area of cells that is an important organizer of the head region.

The notochord is a cylindrical rod of cells that runs along the entire length of the developing embryo.

With signals from the notochord, ectoderm along the mid-dorsal side of the embryo thickens to form the epithelial neural plate (neural folds + neural groove).

The lateral sides of this plate fold upwards, bend and grow toward each other medially – till fuse together, to form the neural tube.

Neurenteric canal – temporary communication between the Amniotic Cavity to the Primitive Yolk sac.

Amniotic fluid above à Primitive yolk Sac below. The Notochondral tube has one opening at the Amniotic fluid, and another opening at the Primitive yolk sac (as a result of fusion between the Notochondral tube and the Endoderm cells).

And so fluid can move between the two cavities à Neurenteric canal.

One side of the disk that is going to develop Nervous system to the side that is going to develop GIT.

Answer 10

Formation of the Notochord:

Cells that miagrate from primative node/pit

• 1st wave: will give rise to the prechordal plate
  
  • thickened of the endoderm that is in contact with ectoderm
  • first cell population migrated from primative node.
  • induction role in formbrain development
• 2cd wave: prenotochordal cells, (precusor notochordal process)

Summary of stages of notochord formation:

• Prenotochordal cells invaginating from the primitive node through the primitive pit move forward cephalic end until they reach the prechordal plate.
• The cells form a a tube – called the notachord process. (from the pit to the prechordal plate)
• The cells of the notachord process floor fuse with hypoblast and dissolve to create neurenteric canal.
  
  • ​This temporary canal that connects the amnionic cavity with the definitive yolk sac.
• The cells proliferate and detach from the endoderm, the cells rises above the endoderm
• The cells proliferate and form a solid cord the definitive notochord.

Question 11

Development of the mesoderm and its differentiation

​

Lateral plate mesoderm: splits into parietal and visceral layers, which line the intraembryonic cavity and surround the organs, respectively.

Parietal Layer:

Mesoderm from the parietal layer, together with overlying ectoderm, will form the lateral and ventral body wall.

Mesoderm cells of the parietal layer surrounding the intraembryonic cavity will form thin membranes – the mesothelial serous membranes, which will line the peritoneal, pleural, and pericardial cavities and secrete serous fluid.

Visceral layer:

Alongside with the embryonic endoderm will form the wall of the gut.

Mesoderm cells of the visceral layer will form a thin serous membrane around each organ.

Circulatory system.

The definitive hematopoietic stem cells arise from mesoderm surrounding the aorta in a site called the aorta-gonad-mesonephros region. These cells will colonize the liver, which becomes the major hematopoietic organ of the fetus. Later, stem cells from the liver will colonize the bone marrow, the definitive blood-forming tissue.

Answer 11

Developing structure from Mesodermal Germ Layer

• Initially, cells of the mesodermal germ layer form a thin sheet of loosely woven tissue on each side of the notocord.
• (day 17, Neural plate - thickening of the ectodermabove the notochord)
• As neural tube begins to form the mesoderm rise on both sides of the midline, proliferate and form a thickened plate of tissue known as paraxial mesoderm.
• Laterally to the risen paraxial mesoderm, there is a thin layer that remains un-changed and is now called lateral plate.
• Intermediate mesoderm- connects paraxial and lateral plate mesoderm
• (day 19, Neuralfolds are developing by cell proliferation on lateral margins of the neural plate.)
• Day 20-12: Inside of the lateral plate intercellular cavities appear.
• These cavitis slowly grow and connect until they divided the tissue into two layers: intraembryonic
  
  • Somatic or parietal mesoderm layer:
    
    • a layer continuous with mesoderm covering the amnion.
  • Splanchnic or visceral mesoderm layer
    
    • A layer continuous with mesoderm covering the yolk sac
• Together, these layers line a newly formed cavity, the intraembryonic cavity, which is continuous with the extraembryonic cavity on each side of the embryo
  
  • primordium of the body cavity

INTRAEMBRYONIC MESODERM

Paraxial – somites

• dermatome (mesenchyme - dermis)
• myotome (myoblasts – skeletal muscles)
• sclerotome (mesenchyme – vertebral development)
• somitomeres, precursors to somites
• Each somitomere consists of mesodermal cells arranged in concentric turbulent around the center of the unit.
• Somitomeres first appear the cephalic region of the embryo, and their formation proceeds cephalocaudally.
• Neuromeres- form in the head region by somitomeres associated with the neural plate segments; this will give rise to mesenchyme in the head.
• From the occipital region caudally, somitomeres further organize into somites.
• The first pair of somites arises in the occipital region of the embryo at approximately the 20th day of development.
• From here, new somites appear in craniocaudal sequence at a rate of approximately three pairs per day until, at the end of the fifth week, 42 to 44 pairs are present.

Intermediate mesoderm ​​

• Differentiates into urogenital structures.
• Cervical and upper thoracic regions:
  
  • forms segmental cell clusters
  • future nephrotomes)
• Caudally
  
  • unsegmented mass of tissue
  • mesonephric blastema,…the nephrogenic cord
  • kidney development (pronefros, mesonefros, metanefros)???
• Most caudal part:
  
  • partly unsegmented
  • Excretory units of the urinary system and the gonads

Lateral plate mesoderm

• somatic (parietal) and splanchnic (visceral)
• mesothelium, mesenchyme

(Notochordal process)

• notochord, neural induction, development of the
• vertebral column

Somite changes:

• In the 4th week, the somite structure is changing and is not a compact ball any more:
• Cells of ventral and medial somite walls:
  
  • arrangement and migrate in the direction of the notochord. These cells are now called
  • sclerotome.
  • sclerotome form a loosely woven tissue, the mesenchyme. They will surround the spinal cord and notochord to form the vertebral column.
• Cells at the dorsolateral portion of the somite:
  
  • also migrate as precursors of the limb and body wall musculature.
• Cells at the dorsomedial portion of the somite:
  
  • Dorsomedial cells migrate beneath the remaining dorsal epithelium of the somite to form the myotome.
• The remaining dorsal epithelium forms the dermatome myotome and dermatome together form dermomyotome.
• • • Each myotome contributes to muscles of the back (epaxial musculature).
• Dermatomes forms the dermis and subcutaneous tissue of the skin.
• • each myotome and dermatome retains its innervation from its segment of origin, no matter where the cells migrate!!
• Hence each somite forms its own:
• sclerotome (the cartilage and bone component)
• myotome (providing the segmental muscle component
• dermatome, the segmental skin component.
• • Each myotome and dermatome also has its own segmental nerve component.

Question 12

Origin and further development of the mesenchyme

Answer 12

DEVELOPMENT OF THE MESENCHYME

• Mesenchyme is loosely organized embryonic connective tissue differentiating mainly from the mesoderm of the:
  
  • dermatomes (CT of the skin)
  • sclerotomes (axial skeleton),
  • somatic
  • and splanchnic mesoderm layers (differentiating into mesenchyme and mesothelium)
• Ectomesenchyme
  
  • is derived from the neural crest cells
    
    • in the head region of the embryo
  • Mainaly populating the phrayngeal archs
  • Epithelio-mesenchymal transformation – cells release from the epithelium, differentiate into elongated or star-shaped cells with cytoplasmic processes, mesenchymal cells are able to migrate????

Mesenchyme is important for the development:

• Presusure for all types of the connective tissue
• blood – mesoblast period of the hemopoesis
  
  • mesoblast periood of hemopoesis
  • formation of stem cells within mesnchyme
• smooth muscles, blood and lymphatic vessels

Question 13

Development of the neuroectoderm and its differentiation

Neural crest and its differentiation

Answer 13

Nrutolation

Neural induction

• Notochord and the prechordal mesoderm stimulates the overlying surface ectoderm to form neural plate.
• Cells of NP make up the neuroectoderm and their induction represents the initial event of neurolation

Molecular regulation of neural induction

• Upregulation of fibroblast growth factor (FGF) together with inhibition of bone morphogenetic protein 4
  
  • (BMP 4 is responsible for ventralizing ectoderm and mesoderm, inhibition of this allow formation of neuroectoderm)
  • Causes induction of the NP.
• Secretion of noggin, chordin, and follistatin by the primitive node, notochord, and prechordal mesoderm:
  
  • Block the inhibitory influence of the BMP.
  • But these neural inducers induce only forebrain and midbrain.
  • Induction of caudal NP structures (hindbrain and spinal chord) depends on WNT3a and FGF.
• In addition, retinoic acid play a role in the organizing the cranial-to-caudal axis by regulating expression of homeobox genes.

Differentiation of the neuroectoderm is accompanied by changes in the distribution of the cell adhesion molecules on the surface of the ectodermal cells.

• Neuroepithelial cells lose E-cadherin and express only N-cadherin,
• whereas the non-induced ectodermal cells lose N-cadherins and retain E-cadherins.

FORMATION OF THE NEURAL PLATE

• Neural plate gives rise to the CNS.
• It appears around the middle of the third week as a slipper-shaped plate, in the mid-dorsal region in front of the primitive node.
• Contains diffrent population of cells, do the the diffrent concentration of growth factors
  
  • The pre-neural crest cells
    
    • First induced in the region of the border of the neural plate.
  • Cells that give ride to neural tube

Development of the neural tube and neural crest: neurulation

• Shortly after neuronal induction the lateral edges of the neural plate elevate to form neural folds and neural plate deepens into neural groove.
• Gradually neural folds approach each other and fuse into neural tube.

Fusion of the neural folds - formation of the neural tube

• Neural folds approach each other in the midline, and finally fuse to form neural tube.
• Fusion begins in the cervical region and proceeds in the cephalic and caudal directions.
• Open ends of the neural tube form anterior and posterior neuropores.
  
  • Closing of the anterior neuropore occurs approximately on the 25th day;
  • the posterior neuropore closes two days later (on the 27th day).

Neural tube defects

• Result from a failure in closing of the neural tube, which causes congenital malformations of the spinal cord and brain.
• NTDs may involve meninges, vertebrae, muscles, and skin.
• Spina bifida is a general term for NTDs affecting the spinal region.
• Occurrence of NTDs has been reduced significantly following folic acid administration

NEURAL TUBE AND ITS DIFFERENTIATION (CNS)

• The cylindrical caudal portion of the neural tube
  
  • becomes spinal cord
• The cephalic end is dilated into three primary brain vesicles:
  
  • forebrain - prosencephalon
  • midbrain - mesencephalon
  • hindbrain – rhombencephalon
• Simultaneously two flexures are form: (bendings)
  
  • cephalic (at the level of midbrain)
  • cervical (at the boundary between the hindbrain and spinal cord).
• By the fifth week
  
  • the three-part brain consists of five parts:
  • Prosencephalon is subdivided into:
    
    • Telencephalon formed by midportion – telencephalon impar, and two primitive cerebral hemispheres
    • Diencephalon (characterized by outgrowth of the optic vesicles)
  • Mesencephalon
  • Rhombencephalon is composed of:
    
    • Metencephalon, which later form pons and cerebellum
    • Myelencephalon, separated by pontine flexure

NEURAL CREST

• The neural crest is first induced in the region of the border of the neural plate.
• As the neural fold elevate and fuse, neuroectodermal cells lying along the crest of each fold separate (pinch off) and form flattened mass between the dorsal surface of the neural tube and surface ectoderm
• Neural crest cells are a transient, multipotent, migratory cell population That contribute to the formation of diverse structures

Directions:

• neural crest cells leaves the neuroectoderm by active migration and enter the underlying mesoderm.
• While migrating the transform from epithelial-to-mesenchyme
• Crest cells from the trunk region leave the neural folds after closure of the neural tube and migrate along one of two pathways:
  
  • 1) a dorsal pathway through the dermis, where they will enter the ectoderm through holes in the basal lamina to form:mmelanocytes in the skin and hair follicles
  • 2) a ventral pathway through the anterior half of each somite to become- sensory ganglia, sympathetic and neurons, Schwann cells, and cells of the adrenal medulla.
• Nural crest cells that have migrated before the closure of the tube contribute to the craniofacial skeleton as well as neurons for cranial ganglia, glial cells, melanocytes, and other cell types.

Structures:

• PNS: neurons and glial cells (satellite and Schwann cells) of the sensory, sympathetic and parasympathetic ganglia
• Chromaffine cells of the medulla of suprarenal gland and paraganglia
• Melanocytes
• Calcitonin-producing cells of the thyroid (parafollicular, C-cells)
• Head mesenchyme (ectomesenchyme); most of the skeletal and connective tissue structures of the head and neck region are derived from the neural crest cells
• Sensory (afferent) neurons of the ganglia of the cranial nerves V, VII, IX, and X are also derived from the neural crest
• Meninges of the brain and spinal cord
• Morphogenesis of outflow tract of the heart (prominent contribution of neural crest cells to the truncoconal region)

Question 14

Early development of the cardiovascular system

Answer 14

General:

• Middle of 3rd week
• The first functional system to develop
• When embryo can sustain itself via diffusion
• Cardiac proginator cells
  
  • in epiblast lateral to primitive streak
• The development of blood circulation takes place in two phases:
  
  • Vasculogenesis:
    
    • Development of vessels from blood islands
    • first vessels develop in wall of yolk sack and chorion, outside of embryo proper
  • Angiogenesis
    
    • sprouting of new bessels from old ones
  • Development of primitive heart

​

1. Vasculogenesis

• FGF2 (fibroblast growth factor 2) stimulates the diffenciation of specific stem cells in extraembryonic mesoderm in wall of yolk sac
  
  • yolk sac wall at that time: endoderm and extraextraembryonic mesoderm
• Into menenchyme
  
  • Blood islets: accumilation of mesenchyme which will diffrencitate into hemangioblasts
• ​​VEGF (vascular endothelial growth factor), produced by surrounding mesenchymal cells, leads to differentiation of 2 types of cells from Hemangioblasts ​
  
  • Hemangioblasts cells: bipotential stem cells
    
    • hemopietic lingage
      
      • ​lumen of primitive blood vessel fromed, containing inner population of cells hematopoeitic stem cells forming primitive blood cells
    • ​development of primitive endothelial cells, with transient stage called angioblast
      
      • ​cells from periphry
  • Formation of primary/primitive vascular network in wall of yolk sac
  • This will go though remodeling

2. Angiogenesis

• Set of processes that lead to the connection of primitive blood vessels and the formation of the bloodstream.
• Controlled by growth factors,
  
  • VEGF,
  • TGF-β (transforming growth factor beta),
  • PDGF (platelet- derived growth factor).
• Under the influence of these factors, primitive vessels grow, new branches sprout and entire networks form.
  
  • Interconnection occurs simultaneously
• At the end of the third week, all the individual vascular beds are connected and a primitive blood circulation is formed .
  
  • dirrentiation into arteries and viens is regulated by the various growth factors

Development of primitive heart

late presomite human embryo: D18

intraembryonic splanchic mesoderm

A- Primary heart field:

• Cardiogenic proginator cells
  
  • located in epiblast adjacent to cranial edge of primative streak
  • miagrate within mesonderm (during gastrulation)
  • to the splanchnic layer of the lateral plate mesoderm
• Forming the primary heart field- cardial crest with proginator cells. horshoe shape

B- Formation of the primitive heart tube

• ​Angiogenic clusters- form lumen- form paired endothelial tubes: primitive pericardial tube (surrounded by splanchnic mesoderm)
  
  • ​innitialy the ptimitve heart is only lined by endothelium
  • later the tube diffrencitates to form myocardium (diffrenciation of myoblasts) and epicardium
• Craniocaudal bending (end of 3rd week):
  
  • At first heart is in the front: rostrally
  • Embryonic folding: to a more ventral/caudal possition and then middle of 4th week it will be localized
  • There is also folding in transversal section:
    
    • The two endocardial tubes approach until they merge in the midline, resulting in a uniform cardiac tube
      
      • caudal most region dosent merge
• Wall of the primitive heart tube consists of
  
  • Endocardium (endothelium) invested by cardiac jelly
    
    • Rich in hylouric acid:
    • Will dissapear as myocardium expands
    • Separates the endocardium from the myocardium and gives rise to the cardiac conduction system
  • Myocardium (myoblasts)
  • Epicardium

UP UNTIL HERE IS PRIMITIVE HEART DEVELOPMENT

• The foundations of the first arteries protrude cranially into the heart tube and the foundations of the first veins enter caudally.
• Division of heart tube:
  
  • Sinus venosus (doubled)
    
    • caudal part
  • Primitive atrium
    
    • constriction (sulcus atrioventricularis)
      
      • will become tricuspid and mitral valve
  • Primitive ventriculus
    
    • constriction: bulboventricular sulcus
      
      • interventricular foramen
  • Bulbus cordis
    
    • will become outflow tract of both ventricles
  • Truncus arteriosum
    
    • pulmonary trunk and aortic roots
• End of the fourth week: a one-way flow of blood.

C- Formation of cardiac loop

• The rotation of the heart tube takes place in several directions:
  
  • Bulbus cordis rotates to the right and down,
  • Area of ​​the atrium and the sinus venosus rotates to the left and up
  • This forms the basis for the final shape of the heart.
  • The process is completed on day 28 .

D- Fetal heart

• After septation, the embryonic heart changes to fetal.
• The fetal heart has separate two chambers, the outflow compartment of the heart.
• A small opening, the foramen ovale , remains in the atrial septum , thanks to which communication between the two halls is maintained.
• This is important for the specific blood circulation of the fetus .

SEPTATION PROCESS?

Question 15

Primitive blood circulation

FIRST PART OF CARDIO DEVELOP

Answer 15

General:

• Middle of 3rd week
• When embryo can sustain itself via diffusion
• Cardiac proginator cells
  
  • in epiblast lateral to primitive streak
• The development of blood circulation takes place in two phases:

1. Vasculogenesis

• FGF2 (fibroblast growth factor 2) differentiates and forms hemangioblasts , which form clusters called islets.
• VEGF (vascular endothelial growth factor), produced by surrounding mesenchymal cells, leads to differentiation of
  
  • superficial cells: primitive endothelial cells, called angioblasts.
  • internal cell: blood/hemopoetic stem cells ​

2. Angiogenesis

• Set of processes that lead to the connection of primitive blood vessels and the formation of the bloodstream.
• Controlled by growth factors,
  
  • VEGF,
  • TGF-β (transforming growth factor beta),
  • PDGF (platelet- derived growth factor).
• Under the influence of these factors, primitive vessels grow, new branches sprout and entire networks form.
• Interconnection occurs simultaneously
• At the end of the third week, all the individual vascular beds are connected and a primitive blood circulation is formed .

Primitive blood circulation

• End of 4th week
• Embryo has a primitve functional cardiovascular system
• Heart starts to beat around day 23
  
  • ​This means that there has to be blood localized in these vessles
  • the blood consitsts of interstesial fluid which gets into the vessels
  • there are also blood cells in the vessels:
    
    • which develop in wall yolk sac
    • also in connecting stalk and chorion

Componets of system

• Ventral aorta:
  
  • Gives rise to branchs that run in each pharyngeal arch, aortic arch
    
    • Paired structures on the side of developing neck
    • join at the dorsal side with the dorsal arota, later will fuse
• Dorsal aorta:
  
  • Paired structure
  • Major artery of embryo
  • Distributes blood:
    
    • Thoughout the whole embryo
    • And to extraembryonic structures
  • From dorsal aorta there are mulitple short beanchs which supply the body wall of the embryo
    
    • Found between the somites: intersomitic vessels
• Vitelline artery
  
  • ​branch from dorsal aorta
  • paired
  • supply yolk sac
  • from primitive capillary plexsus
• Umbilical artery:
  
  • ​branch from dorsal aorta
  • enters connecting stalk and enters chorion up until chorionic villi
    
    • maternal blood surrounds chorionic villi
    • fetal blood comes to close contact with maternal bloos, for exchange in waste products
• Blood from embryo proper is carried back to the heart though cardial viens:
  
  • anterior cardial viens
  • posterior cardial viens
  • fuse together to form common cardial viens (ductus tiviary?)
• Veins that bring blood back from extraembryonic structures:
  
  • vitteline veins: from yolk sac
  • umbilical viens: from chorion
    
    • connecting stalk will become umbillical chord
  • enter sinus vinousus
• Primitive heart
  
  • primitive ventricle
  • primitive artium
  • conus bulbus
  • primitve trunk?

DRAW SCHEMATIC DRAWING

EXTRA:

circulation of fetus until birth, changes

changes after labor

Question 16

Development of the facial region, nasal and oral cavity

• Mesenchyme for formation of the head region is derived from:
  
  • Para-axial Mesoderm
  • Lateral plate Mesoder
  • Ectodermal placodes
• Neural crest cells
  
  • Originate in the neuroectoderm of forebrain, midbrain and hindbrain regions.
  • Miagrate into the oharyngeal archs and optic cup
  • They from tissues in these regions, such as: Cartilage, bone, dentin, tendon, dermis, pia and arachnoid, sensory neurons and glandular CT.

Answer 16

Pharyngeal Arches and Clefts: Primitive pharynx OVERVIEW

• 4th and 5th weeks of development
• Pharyngeal arch:
  
  • Bars of mesenchymal tissue (mesoderm) separated by deep clefts (ectoderm)
  • Each arch carries its own cranial nerve
• Pharyngeal pouches
  
  • Form on the endodermal side between the pharyngeal arches, 4 pouchs
  • Give rise to a number of endocrine glands and parts of the middle ear – middle ear cavity
  • Do not establish an open communication with the external clefts.

FACIAL DEVELOPMENT

​The basic morphology of the face is established between the 4th and 10th weeks by the development and fusion of five prominences

Week 4:

• The frontonasal prominence overlying the forebrain
• Associated with the first pharyngeal arches:
  
  • Two maxillary prominences
  • Two mandibular prominences
• All promences are arranged around the Stomodeum = primitive mouth
  
  • Central part of face
  • Oropharyngeal mambrane, behind it lies the pharynx
  • End of 4th week the membrane ruptures
  • communication of outer amniotic cavity with pharynx
• On frontonasal prominence
  
  • Thickening of ectoderm:
    
    • lens placode (laterally)
    • nasal placode (fronal)

Week 5

• Ectoderm at the center of each nasal placode invaginates to form an oval nasal pit
  
  • Dividing the frontonasal prominence into the lateral and medial nasal processes
  • The medial nasal processes, also increase in size, fuse and grows downwards
• Paired maxillary prominences enlarge and grow ventrally and medially
• Mandibular priminence fuse together
• Nasolacrimal groove:
  
  • The groove between the lateral nasal process and the adjacent maxillary prominence
  • also runs between the nasal pit and lens placode

Week 7

• Fused medial nasal processes form the primordium of the bridge and septum of the nose
• the inferior tips of the medial nasal processes expand laterally and inferiorly and fuse to form the intermaxillary process
• The tips of the maxillary prominences grow to meet the intermaxillary process
• and fuse with it.
• Fusion of medial nasal processes with tips of the maxillary prominences
• Nasolacrimal groove: between the lateral nasal process and the adjacent maxillary prominence
  
  • the ectoderm at the floor of this groove invaginates into the underlying
  • mesenchyme to form a tube called the nasolacrimal duct and lacrimal sac. This duct is invested by bone during the ossification of the maxilla.
  • After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity.
• The intermaxillary segment gives rise to structures in the midline
  • Labial component, which forms the philtrum of the upper lip
  • Upper jaw component, which carries the four incisor teeth
  • Palatal component, which forms the triangular primary palate.
• The intermaxillary segment is continuous with the portion of the nasal septum, which is formed by the frontal prominence.
• End of embryonic period
  
  • eyes, were positioned laterally,
  • they move forward

Summary:

• The frontonasal prominence
  
  • forehead
  • part of nose,
  • part of nasal septum
• the lateral
  
  • ala nasi
• medial nasal processes
  
  • apex of nose
  • intermaxillary sement, also apart of upper lip
• Maxillary prominences
  
  • upper lip
  • upper jaw
  • part of palate
• Mandibular prominences
  
  • lower jaw

NASAL CAVITIES

• Week 6
  
  • Nasal placode–>Nasal pits deepen considerably
  • Medial nasal processs start to merge
    
    • the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process
  • Floor and posterior wall of the nasal sac proliferate to form the nasal fin
    
    • A thickened, platelike fin of ectoderm separating the nasal sac from the oral cavity.
• ​​Week 7
  
  • Vacuoles develop in the nasal fin and fuse with the nasal sac
    
    • Enlarging the sac and thinning the fin to a thin membrane which separates the sac from the oral cavity
      
      • Oronasal membrane
  • This membrane ruptures during the 7th week to form an opening called the primitive choana (no further division other than primary palate)
  • The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate (see Fig. 16-19E).

OLFACTORY EPITHLIUM?

SECONDARY PLATE AND ORAL CAVITY

• Primary palate:
  
  • derived from the intermaxillary segment,

Week 7-8:

• (Main part of the definitive palate:
  
  • Formed by two shelf-like outgrowths from the maxillary prominences.)
• Palatine shelves
  
  • Thin medial extensions produced by medial walls of the maxillary prominences
  • Grow downward, parallel to the lateral surfaces of the tongue.
  • End of the 7th week: rotate rapidly upward into a horizontal position and then fuse with each other and with the triangular primary palate to form the secondary palate
  • Fusion occurs near the middle of the palatine shelves and proceeds both anteriorly and posteriorly.
    
    • The central region, where the primary palate and secondary palate meet, is marked by the incisive foramen
  • ​Intramembranous mesenchymal condensations in the anterior portion of the secondary palate form the bony hard palate.
  • In the posterior portion of the secondary palate, myogenic mesenchyme condenses to give rise to the musculature of the soft palate.
• While the secondary palate is forming:
  
  • Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate to form a midline nasal septum (from roof of primitive nasal cavity)
  • Grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline
• The nasal cavity is now divided into:
  
  • Two nasal passages that open into the pharynx behind the secondary palate through an opening called the definitive choana
• The rotation of the palatine shelves has been ascribed to the rapid synthesis and hydration of Hyaluronic acid within the extracellular matrix of the shelves,
• the alignment of the elevated shelves in a horizontal plane may be determined by the orientation of Collagen and mesenchymal cells

FACIAL MUSCLES:

• The facial mimic muscles
  
  • are based on the mesenchyme of the second pair of pharyngeal arches ,
  • so they are innervated from the facial nerve .
• The masticatory muscles
  
  • musculus tensor veli palatini ,
    
    • musculus tensor tympani ,
      
      • musculus mylohyoideus and
      • front abdomen musculus digastricus
  • arise from the first pair of pharyngeal arches and are therefore innervated from the trigeminal nerve .

CLEFT DEFECT

• Common congenital malformations.
• Latin,
  
  • Clefts=schisis
  • and then named according to the site of affliction
    
    • Cheiloschisis (cleft lip)
      
      • The cleft can be unilateral or bilateral, rarely cleft lower lip.
      • It looks like a notch in the upper lip and can reach up to the nose
      • 1:1000 more common males
    • Palatoschisis (cleft palate)
      
      • Failure of the lateral palatine processes to meet and fuse with each other, the nasal septum, and/or with the primary palat,
      • Cleft palate can be with or without cleft lip
      • occurs 1 : 2,500, more common in females
      • Multifactorial inheritance
      • Placement
        
        • Behind incisive foramen
        • Unilateral cleft of the secondary palate
        • Bilateral cleft of the secondary palate
      • in front of incisive foramen
        
        • Complete unilateral/ bilateral cleft of the lip and alveolar process of maxilla
        • Unilateral/bilateral cleft of the primary palate
        • Complete bilateral cleft of the lip and aleveolar process with complete bilateral cleft of the primary and secondary palate
• Gnathoschisis (cleft jaw)
• There may also be combinations of clefts such as
  
  • cheilognathoschisis (cleft lip and jaw)
  • total cleft cheilognathopalatoschisis (cleft lip, palate and jaw).
• In addition to cleft lip, palate, and jaw, there are other types of clefts such as spinal clefts and abdominal wall clefts
• Incidence of cleft defects
  
  • The left side of the face is damaged twice as often as the right side.
  • isolated cleft is more common in girls.
  • Total cleft (ie cleft lip, palate and jaw) is more common in boys,
  • Not the same in both sexes.

OTHER/EXTRA

• At the 4th week, the center of the face is formed by the stomodeum, surrounded by the first pair of pharyngeal arches.
• When the embryo is 42 days, five mesenchymal prominences can be recognized:
  
  • 2 Mandibular prominences: of the first pharyngeal arch.
  • 2 Maxillary prominences: dorsal portion of the 1st pharyngeal arch.
  • 1 Frontonasal prominence: rounded elevation cranial to the stomodeum
• Later, addition 2 nasal prominences are formed

The lower lip and Jaw are formed from the Mandibular prominences that merge across the midline.

Cheeks and Maxillae: formed by the maxillary prominences as they enlarge

The first pharyngeal arch

• Maxillary protrusion: gives rise to the upper jaw
  
  • Pre-maxilla, maxilla, zygomatic bone and part of temporal bone: membranous ossification.
• Mandibular protrusion: forms the lower jaw
  
  • contains Meckel’s Cartilage: disappears except for Incus and Malleus.
• Musculature:
  • includes the muscles of Mastication, anterior belly of digastric, mylohyoid, tensor tympani and tensor palatini.
• Innervation:
  
  • Mandibular branch of trigeminal nerve.

The Second Pharyngeal Arch

• Hyoid arch (Reichert’s Cartilage) gives rise to:
• Bones: Stapes, Styloid process of temporal bone, stylohyoid ligament, and ventrally the lesser horn and upper part of the body of hyoid bone.
• Muscles: Stapedius, Stylohyoid, Posterior belly of Diagastric, auricular and muscles of facial expressions.
• Innervation: the facial nerve is the nerve of the 2nd arch.

The Third Pharyngeal Arch

• Produces the lower part of the body and greater horn of the Hyoid bone.
• Musculature: limited to Stylopharangeus muscles.
• Innervation: Glossopharyngeal nerve, the nerve of the 3rd arch.

Question 17

Development of the tooth

Answer 17

The shape of the face is determined by

• not only by expansion of the paranasal sinuses but
• also by growth of the mandible and maxilla to accommodate the teeth.

Teeth themselves arise from an epithelial-mesenchymal interaction between overlying oral epithelium and underlying mesenchyme derived from neural crest cells.

Week 6

• U-shaped ridge of epidermis called the dental lamina appears on the upper and lower jaws
• Labiogingival lamina (more anterior)
  
  • provides the basis for the upper and lower lip, the inner for the gum.
• Ectoderm lining the lamina

Week 7

• Bud stage:
  
  • Ten centers of epidermal cell proliferation develop at intervals on each dental lamina and grow down into the underlying mesenchyme.
    
    • ​Will be desiduous teeth
• A condensation of mesenchyme appears under and around each of these 20 ingrowths.
• The composite structure consisting of the dental lamina ingrowth and the underlying mesenchymal condensation is called a tooth bud

Week 8

• Cap stage:
  
  • Mesenchyme invades the base of the dental lamina ingrowth- tooth bud
  • Condenses inside cap and around it
    
    • Around: dental sac
      
      • Outer enemel epithlium
    • Inside: dental papilla
      
      • Inner enemel epithlium
    • Ectodermal structure in between the epithlial structures will become reticular epithlium with connections with each other
      
      • Stelate reticulum

Week 14

• dental papilla has deeply invaginated the dental

lamina and constitutes the core of the developing

tooth. This is called the bell stage of tooth development,

because the dental lamina looks like a bell

resting over the dental papilla (Fig. 7-17D, H; see

Teeth themselves arise from an epithelial-mesenchymal interaction between overlying oral epithelium and underlying mesenchyme derived from neural crest cells.

Dental lamina - C-shaped structure, formed by basal layer of the epithelial lining of the oral cavity along the length of the upper and lower jaws. formed by the sixth week.

Dental lamina gives rise to a number of dental buds.

Dental lamina creates - 10 dental buds in each jaw, which form the primitive state of the ectodermalcomponents of the teeth.

Soon the deep surface of the buds invaginates, resulting in the cap stage of tooth development.

Cap stage of tooth development- a cap consists of:

Outer dental epithelium

inner dental epithelium

Stellate reticulum - central core of loosely woven tissue.

The mesenchyme (from neural crest) forms the dental papilla.

As the dental cap grows and the area deepens, the tooth takes on the appearance of a bell (bell stage).

Mesenchyme cells of the papilla near to the inner dental layer differentiate into odontoblasts, which later produce dentin.

With thickening of the dentin layer, odontoblasts retreat into the dental papilla, leaving a thin cytoplasmic process (dental process) behind in the dentin.

throughout the life odontoblast provides predentin

The remaining cells of the dental papilla form the pulp of the tooth.

Question 18

Growth of the conceptus, development of its shape

Childbirth (parturition), signs of the full-term baby

Answer 18

Pregnancy

• Divide prenatal period into 2 parts:
  
  • Embryonic period, first 8 weeks
  • Fetus

Estimation of the age of the embryo (Clalculate length of pregnancy)

• The onset of the last menstruation (280 days)
  
  • +1 year + 7 days – 3 calendar months= get estimated term of labor
• Length of pregnancy: after fertilization (266 days)
• First movements sensed by the mother (18 th -20th week), end of 5th month
• The position (height) of the uterine fundus, into higher possition
• Ultrasound examination

Overal changes in external development

• Quick overview:
  
  • 3 month
    
    • Disproportion between the head and the body
    • Disproportion between the upper and lower extremities
    • Eyelids fused
    • Reposition of the umbilical hernia (intesinal lobe re-enter abdominal cavity)
  • 4 month
    
    • Fast growth, ossification continues
  • 5 month
    
    • Disproportion between the upper and lower extremities disappears,
    • First movements,
    • Fine short hair, eyebrows, lanugo and vernix caseosa (glands/ grease ?) protection of developming skin
    • Brown fat: function to produce heat, for adaptaion of born baby
  • 6 month
    
    • Increase in weight,
    • Eyelids open
  • 7 month
    
    • Development of the white adipose tissue: skin becomes smooth
      
      • the skin becomes smooth
      • premature babies have wrinkeled skin
  • 8 month -
    
    • Development of the subcutaneous tissue
    • nails reach the tips of fingers and toes

Week 4

• Beginning: 2-5 mm embryo is practically straight, with 4-12 somites rising to the surface.
• At the rostral and caudal ends we find a wide neural tube.
• On day 24, pharyngeal arches appear .
• There is a head and caudal fold.
• A heart forming a conspicuous hump in front: heart prominence.
• On the 26th day, three pairs of pharyngeal (gill) arches are visible, the anterior neuroporus is freshly closed.
• The embryo has the characteristic shape of the letter C, the forebrain is formed.
• The long, curved tail is easily visible.
• Day 26-27: the upper limb buds appear on the ventrolateral sides of the body wall.
• The auditory/otic pits on both sides of the head are also visible, together with the endoderm thickening of the lens placode - the ancestor of the eyelenses.
• On the 28th day we find the formation of the fourth pair of pharyngeal arches and lower limb buds.
• Extensive development of dorsal part: somites
• Characteristically, the tail narrows and the posterior neuroporus closes.

Week 6

• Rapid development of the brain
  
  • thus an enlargement of the head and facial protrusions.
• The face thus comes into contact with the bump of the heart.
• The hyoid (second) pharyngeal arch overgrows the third and fourth and forms an endoderm cervical sinus on both sides.
• The upper limb buds take the shape of a paddle, the bases of the lower limbs are fin-shaped.
• Apart from the head and face, the external shape of the embryo does not change much this week.

Week 7

• The main event of this week is a significant change in the limbs.
• Notches appear between the digital beams of the finger discs.
• A yolk stalk is formed, the intestinal loops extend into the proximal part of the umbilical cord - physiological umbilical herniation caused by the disproportion between the small extent of the abdominal cavity and the rapid growth of the intestine.
• Ossification of the skeleton of the upper limbs begins.
• Pigmented eye

Week 8

• Upper limbs are clearly separated, but are proximally connected by a membrane.
• We see scratches between the digital rays of the foot plate.
• A vascular plaque of the scalp forms around the head and forms a band around the top of the head.
• At the end of the eighth week, all parts of the limbs are clearly defined, the fingers are elongated and completely separate from each other.
• Ossification begins on the lower limbs, the hint of the tail disappears.
• The arms and legs approach ventrally.
• By the end of this week, the embryo is already significantly human, but the head is disproportionately large.
• There is a distinct neck and eyelids, which gradually close and at the end of this period the epithelia of the upper and lower eyelids merge (end of the embryonic period).
• The earlobes take on their final shape, but are set low on the head.

Possition of uterine fundus

• 4. month: 2 fingers above symphysis
• 5. month: half-way between symphysis and umbilicus
• 6.month: umbilicus
• 7. month: 3 fingers above the umbilicus
• 8. month: half-way between umbilicus and processus xiphoides
• 9. month: Processus xiphoides
• 10. month: Same as 8. month

Fetal gowth mesurment

• CRL: crown rump
  
  • month^2= exponential growth until 5th month
  • after 5th month+ 5 cm growth
• CHL: crown heal
  
  • For fetuses with developed lower limbs, we measure the length from the crown to the heel
• 6th month: CHL: 30 cm, 640 kg- premature birth that can be saved

Changes in body proportions

• Especially in the embryonic period, the development of individual parts of the body is not proportional.
• Head part of the embryo and the trunk grow.
• End of the embryonic period
  
  • Head is about ½ the length of the whole body and the limbs are relatively short.
• During the fetal period
  
  • Limbs and torso size increase more compared to the size of the head.
• In a newborn,
  
  • Head is about ¼ in total length.
  • Postnatally, this development continues, as the adult head corresponds to 1/8 of the whole body.

Question 19

Childbirth (parturition), signs of the full-term baby

Answer 19

Signs of full-term fetus

• Average weight 3500g, length 50cm
• Well formed subcutaneous fat
  
  • (body contours are rounded)
• The skin is pink, glabrous, only on the shoulders and back there are remnants of lanuga
  
  • Reminants of vernix caseosa
  • Remnants of lanugo hair on the back only
• Fine hair, the nails extend beyond the tips of fingers/toes
  
  • Eyebrows and eyelashes are well formed
• Well-developed external genitalia: testes are in the scrotum, labia majora cover labia minora
• The skull bones are hard, the small and large fontanelles are palpable and separated
• The newborn screams loudly and moves

Labor (parturition)

• First phase – (effacement): opening phase
  
  • Early labor, invoulentary, longest phase
  • Dilation of the cervix
    
    • Uterine wall contracts based on levels of oxtocyin and nerve simulation
    • This pushes the baby and the amnionic fluid against the uterine cervix, which becomes dialated
      
      • There is no muscle in uterine cervix, mostly CT
      • The CT changes its consitency during pregnancy, and becomes softer
      • this allows easier dialation of cervix
  • As labor continues, contractions become longer and more frequent
  • At end of 1st phase
    
    • Cervix is very dilated: cause the sac of fetal membranes (multiplayer structure fused together) break/rupture
      
      • This causes amnionic fluid to leak out
• Second phase ​
  
  • Passage of the fetus through the birth canal
  • The fetus is expelled by uterine contractions and with the participation of the abdominal press.
• Third phase
  
  • Delivery of the placenta and fetal membranes
    
    • It begins with the separation of the placenta from the uterine wall by retractions of the uterine muscles (sudden shortening of the muscle bundles, which prevents bleeding) with subsequent uterine contractions that complete the process.
    • When the placenta sinks into the vagina, it induces the reflective pressure of the abdominal press, which pushes the placenta with the envelopes outward.

Question 20

Development of the Amniotic and Yolk Sacs, Chorion

Answer 20

Second week of development

Day 8:

• At the eighth day of development, the blastocyst is partially embedded in the endometrial stroma.
• Trophoblast has differentiated into two layers:
  
  • cytotrophoblast- inner layer of mononucleated cells
  • syncytiotrophoblast- outer multinucleated zone without distinct cell boundaries.
• Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc:
  
  • FGF: fibroblast growth factor
    
    • Hypoblast layer -
      
      • a layer of small cuboidal cells adjacent to the blastocyst cavity.
    • Epiblast layer -
      
      • a layer of high columnar cells adjacent to the amniotic cavity.
  • Amniotic cavity - a cavity that appears within the epiblast.
    
    • Development of the amniotic cavity : inter-cellular spaces between some cells of the embryoblast enlarge and fuse into cavity (this process is associated also with the apoptosis of single cells).
  • Amnioblasts - Epiblast cells adjacent to the cytotrophoblast.
• The endometrial stroma adjacent to the implantation site is edematous and highly vascular.
  
  • The large, tortuous glands secrete abundant glycogen and mucus.
  • The uterine glands synthesize or transport and secrete substances essential for survival and development of the embryo or fetus and associated extraembryonic membranes.

Day 9

• Surface epithelium at place of implantation is closed by a fibrin coagulum.
• Trophoblast development
  
  • At embryonic pole: vacuoles appear in the syncytium.
  • Lacunar stage: fusion of vacules to form large lacuna
• Embryoblast development
  
  • Exocoelomic (Heuser’s) membrane - flattened cells originating from the hypoblast form a thin membrane that lines the inner surface of the cytotrophoblast.
  • This membrane, together with the hypoblast, forms the lining of the exocoelomic cavity, or primitive yolk sac.

Days 11 and 12

• Blastocyst is completely embedded in the endometrial stroma, and the surface epithelium almost entirely covers the original defect in the uterine wall.
• Trophoblast development
  
  • lacunar spaces evident at the embryonic pole
  • Cells of the syncytiotrophoblast penetrate deeper into the stroma.
  • The lacunae become continuous with the sinusoids (Maternal capillaries, which are contacted and dilated) and maternal blood enters the lacunar system.
  • Uteroplacental circulation -
    
    • As the trophoblast continues to erode more and more sinusoids, maternal blood begins to flow through the trophoblastic system, establishing the uteroplacental circulation.
• Embryoblast development
  
  • ​Extraembryonic mesoderm-
    
    • Derived from yolk sac cells, appears between the inner surface of the cytotrophoblast and the outer surface of the exocoelomic cavity.
      
      • Loose connective tissue.
    • This tissue fills all of the space between the trophoblast externally and the amnion and exocoelomic membrane internally.
  • Large cavities develop in the extraembryonic mesoderm, and when these become confluent, they form a new space known as the extraembryonic coelom, or chorionic cavity.
    
    • This space surrounds the primitive yolk sac and amniotic cavity except where the germ disc is connected to the trophoblast by the connecting stalk.
    • Extraembryonic somatic mesoderm- line’s the cytotrophoblast and amnion. (outer)
    • Extraembryonic splanchnic mesoderm- the lining covering the yolk sac
• Bilaminar blastocyst or Bilaminar disc -the epiblast and the hypoblast, evolved from the embryoblast.
  
  • These two layers are sandwiched between two balloons:
    
    • The primitive yolk sac
    • The amniotic cavity.

Day 13

• Occasionally, bleeding occurs at the implantation site as a result of increased blood flow into the lacunar spaces.
  
  • Because this bleeding occurs near the 28th day of the menstrual cycle, it may be confused with normal menstrual bleeding and, therefore, cause inaccuracy in determining the expected delivery date.
• Trophoblast development:
  
  • Is characterized by villous structures.
  • Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by syncytium.
  • Primary villi - Cellular columns of cytotrophoblast with the syncytial covering.
• Embryoblast development
  
  • Formation of the extraembryonic coelom and its enlargement lead to reduction of the cavity of the primary yolk sac (forming the secondary yolk sac).
  • Endodermal cells (yellow) proliferate along the inner surface of exocoelomic membrane and form the wall of the secondary YS. Remnants of the exocoelomic cavity persist as exocoelomic cysts
    • = secondary yolk sac or definitive yolk sac.
      
      • This yolk sac is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• During its formation, large portions of the exocoelomic cavity are pinched off. These portions are represented by exocoelomic cysts, which are often found in the extraembryonic coelom or chorionic cavity.
• Meanwhile, the extraembryonic coelom expands and forms a large cavity, the chorionic cavity.
• The extraembryonic mesoderm lining the inside of the cytotrophoblast is then known as the chorionic plate.
• The only place where extraembryonic mesoderm traverses across the chorionic cavity is in the connecting stalk.
• With development of blood vessels, the stalk becomes the umbilical cord. –

Question 21

Development of chorionic villi, hemoplacental barrier

FORMATION OF FETAL MEMBRANES

Formation of the fetal membranes:

• Also known as extraembryonic membranes
  
  • (i.e., amnion, chorion, yolk sac, and allantois)

**********************************************

Overview and opening

Prenatal perod: intrauterine development after fertilization of the ovum by sperm up until delivery

• Fertilization (→Zygote)
• Blastogenesis: first 2 weeks after fertilization
• Embryonic period: until end of 8th week (basis of organs are formed)
• Fetal period: until childbirth (growth and functional maturation of organs)

Week 1 of development:

• Ferrtilization→ Zygote→ Cleavlage (repeated mitotic division)→Blastomere (daugter cell of zygote) →Morula (16 cells)→ Blastocyst (inner and outer mass, cavity)→
  
  • Inner cell mass→ embryo proper: embryoblast
  • Outer cell mass→ trophoblast(which later contributes to the placenta.) ​
• Implantation beggins around day 6

Week 2 of development:

• Blastocyst is partially embedded in the endometrial stroma.
• Trophoblast differentiated into two layers:
  
  • Cytotrophoblast- inner layer of mononucleated cells
    
    • Will produce the primary chorionic villi, by protruding into syncytiotrophoblast
  • Syncytiotrophoblast- outer multinucleated zone without distinct cell boundaries.
    
    • The ​periphery the syncytiotrophoblast forms a syncytium
    • multi-nucleic layer without cell boundaries that arises from the fusion of cytotrophoblast cells
  • Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc
    
    • ​Hypoblast and epiblast
    • Two layers are sandwiched between cavities
      
      • Blastocyst cavity→ The primitive yolk sac
      • The amniotic cavity
        
        • Is hollowed out from the middle of the inner cell mass (epiblast part of embryoblast)
        • Amnioblasts: epiblast cells adjacent to the cytotrophoblast
• ​Day 9:
• Surface epithelium at place of implantation is closed by a fibrin coagulum.
• Lacunar stage:
  
  • Vacuoles appear in the syncytium→ fusion of vacules to form large lacuna

​****************************************

Formation of the fetal membranes: extraembryonic membranes

amnion, chorion, yolk sac, and allantois

• Formation of the Amnionic cavity
  
  • Bilaminar disc: Hypoblast and epiblast
  • Space between cytotrophoblast and epiblast is hollowed out
    
    • Amnioblasts: epiblast cells adjacent to the cytotrophoblast
• Formation of the yolk sac and chorion
  
  • Primative yolk sac
    
    • Proliferation of hypoblast cells→ extend around the blastocyst cavity→ forming the exocoelomic membrane, or Heuser’s membrane: Primative yolk sac
  • Definative yolk sac (secondary) and chorion
    
    • Formation of extraembryonic mesoderm (derived from yolk sac cells) appears between:
      
      • The inner surface of the cytotrophoblast
      • The outer surface of the exocoelomic cavity.
        
        • Loose connective tissue.
    • Large cavities develop in the extraembryonic mesoderm→ causing the mesoderm to split and displacment of primary yolk sac→
      
      • (Outer) extraembryonic somatic mesoderm:
        
        • Lines the cytotrophoblast and amnion
      • (Inner) extraembryonic splanchnic mesoderm:
        
        • The lining covering the yolk sac
    • A new space—the extraembryonic coelom, or chorionic cavity—forms by splitting of the extraembryonic mesoderm into two layers.
      
      • This cavity separates the embryo with its attached amnion and yolk sac from the outer wall of the blastocyst
      • Seperation occurs everywhere except the connecting stalk
    • Formation of the chorionic cavity and its enlargement lead to reduction of the cavity of the primary yolk sac:
      
      • A second wave of migration of hypoblast cells produces a new membrane that migrates out over the inside of the extraembryonic mesoderm (splanchnic) pushing the primary yolk sac in front of it.
        
        • This new layer becomes the endodermal lining of the secondary (definitive) yolk sac.
      • Chorionic cavity continues to enlarge
        
        • Remnants of the primary yold sac persist as exocoelomic cysts
      • The secondary yolk sac or definitive yolk sac: is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• Summary:
  
  • Definative yolk sac:
    
    • Extraembryonic endoderm
    • (Inner) extraembryonic splanchnic mesoderm
  • ​Connecting stalk: ???
    
    • ​​extraembryonic splanchnic mesoderm
  • Amnionic cavity
    
    • Amnioblasts and embryonic disc​
  • Chorionic plate
    
    • Extraembrionic somatic mesoderm,
    • Extraembryonic ectoderm
      
      • Cytotrophoblast
      • Syncytiotrophoblast
• The definitive yolk sac
  
  • Remains a major structure associated with the developing embryo through the 4th week and performs important early functions.
    
    • Extraembryonic mesoderm forming the outer layer of the yolk sac is a major site of hematopoiesis- blood formation
    • primordial germ cells can first be identified in humans in the wall of the yolk sac.
  • After the 4th week, the yolk sac is rapidly overgrown by the developing embryonic disc.
    
    • The yolk sac normally disappears before birth, but on rare occasions it persists in the form of a digestive tract anomaly called Meckel’s diverticulum

****************

Answer 21

Overview:

Summary: The second week of development is known as the week of the twos…

• The trophoblast differentiates into two layers:
  
  • Cytotophoblast
  • Syncytiotrophoblast.
• The embryoblast forms two layers:
  
  • Epiblast
  • Hypoblast.
• The extraembryonic mesoderm splits into two layers:
  
  • (Outer) extraembryonic somatic mesoderm:
    
    • Lines the cytotrophoblast and amnion
  • (Inner) extraembryonic splanchnic mesoderm:
    
    • The lining covering the yolk sac
• Two cavities
  
  • Amniotic
  • Yolk sac

Outer fetal membrane is called Chorion, inner fetal membrane is called Amnion.

Syncytiotrophoblast – producing the human chorionic gonadotropin (hCG) into the maternal blood – to the kidneys – into the urine.

1. Development of chorionic villi, hemoplacental barrier

Thrid week of development

• Further Development of the Trophoblast
  
  • Day 9: Lacunar stage:
    
    • Vacuoles appear in the syncytium→ fusion of vacules to form large lacuna
  • Days 11 and 12: The lacunae become continuous with the sinusoids (Maternal capillaries, which are contacted and dilated) and maternal blood enters the lacunar system.
• By the beginning of the third week:
  
  • Primary Villi -
    
    • Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by syncytium.
    • Primary villi - Cellular columns of cytotrophoblast with the syncytial covering.
• During further development
  
  • Mesodermal cells penetrate the core of primary villi and grow toward the decidua→
    
    • Secondary villi
      
      • Newly penetrated mesoderm core
      • Cytotrophoblastic layer
      • Syncytial layer
• By the end of the third week
  
  • Mesodermal cells in the core of the villus begin to differentiate into blood cells and small blood vessels→ ​
    
    • forming the villous capillary system
• Tertiary villus or definitive placental villus
  
  • ​The villi after the formation of the villous capillary system
  • Capillaries in tertiary villi make contact with capillaries developing in:
    
    • Mesoderm of the chorionic plate
    • Connecting stalk
    • forming the extraembryonic vascular system
• These vessels, in turn, establish contact with the intraembryonic circulatory system, connecting the placenta and the embryo.
  
  • When the heart begins to beat in the fourth week of development, the villous system is ready to supply the embryo with essential nutrients and oxygen.
• Meanwhile, cytotrophoblastic cells in the villi penetrate progressively into the overlying syncytium until they reach the maternal endometrium.
  
  • They establish contact with similar extensions of neighboring villous stems, forming a thin outer cytotrophoblast shell.
    
    • Gradually surrounds the trophoblast entirely and attaches the chorionic sac firmly to the maternal endometrial tissue.
• Anchoring villi:
  
  • Extend from the mesoderm of the chorionic plate to the cytotrophoblast shell reaching thr decidua basalis
• Branch chorionic villi:
  
  • The villi that grow from the sides of the stem villi (terminal villi??).
  • The branches of the villi are the location where the true exchange of material between the blood of the mother and the embryo takes place.

Placenta

The decidua plate (decidua basalis),

The chorion plate (chorion frondosum)

And the the villi system in-between

Circulation of the placenta

Cotyledons receive their blood through 80 to 100 spiral arteries

Pierce the decidual plate

Enter the intervillous spaces at more or less regular intervals

The lumen of the spiral artery is narrow, so blood pressure in the intervillous space is high.

This pressure forces the blood deep into the intervillous spaces and bathes the numerous small villi of the villous tree in oxygenated blood.

As the pressure decreases, blood flows back to the endometrial veins.

Collectively, the intervillous spaces of a mature placenta contain approximately 150 ml of blood, which is replenished about 3 or 4 times per minute.

This blood moves along the chorionic villi, which have a surface area of 4 to 14 m2.

Placental exchange does not take place in all villi
Only villi that lost some of there coverings:

degeneration of cytotrophoblast cells

And are in contact with syncytial membraneThe placental membrane, which separates maternal and fetal blood, is initially composed of four layers:

(a) the endothelial lining of fetal vessels
(b) the connective tissue in the villus core
(c) the cytotrophoblastic layer
(d) the syncytium.

From the fourth month on, however, the placental membrane thins, thus greatly increasing the rate of exchange.

Sometimes called the placental barrier, the placental membrane is not a true barrier, since many substances pass through it freely.

Because the maternal blood in the intervillous spaces is separated from the fetal blood by a chorionic derivative, the human placenta is considered to be of the hemochorial type.

Hemochorial- type of placenta in which maternal blood comes in direct contact with the chorion)

Maternal blood is delivered to the placenta by spiral arteries in the uterus. Erosion of these maternal vessels to release blood into intervilllous spaces is accomplished by endovascular invasion by cytotrophoblast cellsà

These cells, released from the ends of anchoring villi, invade the terminal ends of spiral arteries, where they replace maternal endothelial cells in the vessels walls, creating vessels containing both fetal and maternal cells. To accomplish this process, cytotrophoblast cells undergo epithelial to endothelial transition.

During the following months, numerous small extensions grow out from existing stem villi and extend as free villi into the surrounding intervillous spaces (lacunar spaces). The syncytium and endothelial wall of the blood vessels are then the only layers that separate the maternal and fetal circulations.

By the end of the 3rd week, embryonic blood begins to flow slowly through the capillaries in the chorionic villi.

Oxygen and nutrients in the maternal blood in the intervillous space diffuse through the walls of the villi and enter the embryo’s blood

Carbon dioxide and waste products diffuse from blood in the fetal capillaries through the wall of the villi into the maternal blood.

Villi that attach to the maternal tissues through the cytotrophoblastic shell are called stem chorionic villi (anchoring villi).

The villi that grow from the sides of the stem villi are called branch chorionic villi (terminal villi). It is through the walls of the branch villi that the main exchange of material between the blood of the mother and the embryo takes place.

The branch villi are bathed in continually changing maternal blood in the intervillous space

• decidual plate: the part of the endometrium where the placenta will form
• • Those that branch from the sides of stem villi are free (terminal) villi, through which exchange of nutrients and other factors will occur.
• • The chorionic cavity, becomes larger, and by the 19th or 20th day, the embryo is attached to its trophoblastic shell by a narrow connecting stalk.
• The connecting stalk later develops into the umbilical cord, which forms the connection between placenta and embryo.

Chorionic plate - consist of:

extraembrionic somatic mesoderm

cytotrophoblast

syncytiotrophoblast

• Meanwhile, cytotrophoblastic cells in the villi penetrate progressively into the overlying syncytium until they reach the maternal endometrium.
  
  • Here they establish contact with similar extensions of neighboring villous stems, forming a thin outer cytotrophoblast shell.
  • This shell gradually surrounds the trophoblast entirely and attaches the chorionic sac firmly to the maternal endometrial tissue. Villi that extend from the chorionic plate to the decidua basalis are called stem or anchoring villi.

decidual plate: the part of the endometrium where the placenta will form

Those that branch from the sides of stem villi are free (terminal) villi, through which exchange of nutrients and other factors will occur.

The chorionic cavity, becomes larger, and by the 19th or 20th day, the embryo is attached to its trophoblastic shell by a narrow connecting stalk.

The connecting stalk later develops into the umbilical cord, which forms the connection between placenta and embryo.

→

• • The endometrial stroma adjacent to the implantation site is edematous and highly vascular.
    
    • The large, tortuous glands secrete abundant glycogen and mucus.
    • The uterine glands synthesize or transport and secrete substances essential for survival and development of the embryo or fetus and associated extraembryonic membranes.

​Days 11 and 12

• • The lacunae become continuous with the sinusoids (Maternal capillaries, which are contacted and dilated) and maternal blood enters the lacunar system.
    
    • Uteroplacental circulation -
      
      • As the trophoblast continues to erode more and more sinusoids, maternal blood begins to flow through the trophoblastic system, establishing the uteroplacental circulation.

Day 13

• Occasionally, bleeding occurs at the implantation site as a result of increased blood flow into the lacunar spaces.
  
  • Because this bleeding occurs near the 28th day of the menstrual cycle, it may be confused with normal menstrual bleeding and, therefore, cause inaccuracy in determining the expected delivery date.
• Trophoblast development:
  
  • Is characterized by villous structures.
  • Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by syncytium.
  • Primary villi - Cellular columns of cytotrophoblast with the syncytial covering.
• Embryoblast development
  
  • Formation of the extraembryonic coelom and its enlargement lead to reduction of the cavity of the primary yolk sac (forming the secondary yolk sac).
  • Endodermal cells (yellow) proliferate along the inner surface of exocoelomic membrane and form the wall of the secondary YS. Remnants of the exocoelomic cavity persist as exocoelomic cysts
    • = secondary yolk sac or definitive yolk sac.
      
      • This yolk sac is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• During its formation, large portions of the exocoelomic cavity are pinched off. These portions are represented by exocoelomic cysts, which are often found in the extraembryonic coelom or chorionic cavity.
• Meanwhile, the extraembryonic coelom expands and forms a large cavity, the chorionic cavity.
• The extraembryonic mesoderm lining the inside of the cytotrophoblast is then known as the chorionic plate.
• The only place where extraembryonic mesoderm traverses across the chorionic cavity is in the connecting stalk.
• With development of blood vessels, the stalk becomes the umbilical cord. –

The outer wall of the blastocyst is now called the chorion.

• Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc:
  
  • FGF: fibroblast growth factor
    
    • Hypoblast layer -
      
      • a layer of small cuboidal cells adjacent to the blastocyst cavity.
    • Epiblast layer -
      
      • a layer of high columnar cells adjacent to the amniotic cavity.

Question 22

Development and anomalies of placenta

Structure of placenta

Decidual reaction:

Change of endometrium: Zona functionalis

• Multiplication of vessels
• Increaded activity of uterine glands
  
  • Glandular cells increase in volume
  • Cytoplasm is vaculized
  • Ncl is enlarged and very dark
• Decudial cells
  
  • form from the transormation of the lamina propria fibroblasts
  • Produces immoprotective enviorment

Answer 22

Opening: By the beginning of the second month

• Trophoblast is characterized by a great number of secondary and tertiary villi.
• The villi are coming from the chorionic plate and are attached peripherally to the maternal decidua by way of the outer cytotrophoblast shell.
  
  • Cytotrophoblast shell
    
    • Cytotrophoblast is penetrating through the syncitiotrophoblast and creats a shell covering the interlacunar system and attaches on the maternal surface of the decidua basalis.
  • Chorionic plate
    
    • ​Consist of:
      
      • Extraembrionic somatic mesoderm
      • Cytotrophoblast
      • Syncytiotrophoblast
  • Villi is formed by:
    
    • core of vascular mesoderm
    • cytotrophoblastic cells
    • syncytium
• Capillary system is developing in the villous than comes in contact with capillaries of the chorionic plate and connecting stalk, thus giving rise to the extraembryonic vascular system.
• During the following months,
  
  • Numerous small extensions sprout from existing villous stems into the surrounding lacunar or intervillous spaces.

Beginning of the fourth month,

• Cytotrophoblastic cells and some connective tissue cells disappear.
• The syncytium and endothelial wall of the blood vessels are then the only layers that separate the maternal and fetal circulations.
  
  • (in this process the placenta membrane is destroyed)

CHORION FRONDOSUM AND DECIDUA BASALIS

• In the early weeks of development, villi cover the entire surface of the chorion.
  
  • Embryonic pole
    
    • As pregnancy advances, villi continue to grow and expand, giving rise to the chorion frondosum (bushy chorion).
    • Chorion frondosum- chroion covered with extensive villi
  • Abembryonic pole
    
    • Villi degenerate and by the third month this side of the chorion, now known as the chorion laeve, is smooth.
  • The difference between the embryonic and abembryonic poles of the chorion is also reflected in the structure of the
• Decidua=the functional layer of the endometrium, which is shed during birth.
  
  • Decidua basalis
    
    • The decidua over the chorion frondosum.
    • Consists of a compact layer of large cells, decidual cells, with abundant amounts of lipids and glycogen.
    • Tightly connected to the chorion
    • Decidua plate: the part next to the the basalis which will contribute to placenta)
  • Decidua capsularis- (chorion laeve)
    
    • The decidual layer over the abembryonic pole.
    • With growth it becomes stretched and degenerates.
  • Decidua parietalis-
    
    • The decidual layer in contact with the uterine wall, opposing the abembryonic pole
  • Subsequently, the chorion laeve comes into contact with the uterine wall (decidua parietalis) on the opposite side of the uterus and the two fuse, obliterating the uterine lumen.
    
    • Fusion of the amnion and chorion accurse to form the amniochorionic membrane obliterates the chorionic cavity.
      
      • It is this membrane that ruptures during labor (breaking of the water).
      • When this amniochorionic membrane expend the decidua capsularis rapture and degenerate.
      • Amniochorionic membrane comes in touch with decidua parietalis (uterine wall), basically the entire uterine cavity desapere.

Placenta

• The decidua plate (decidua basalis),
• The chorion plate (chorion frondosum)
• And the the villi system in-between

By the beginning of the fourth month, the placenta has two components:

• (a) fetal portion, formed by the chorion frondosum.
• (b) maternal portion, formed by the decidua basalis.
• Junctional zone
  
  • Area in which trophoblast and decidua cells intermingle.
  • Characterized by decidual and syncytial giant cells
  • Rich in amorphous extracellular material.
• By this time:
  
  • Most of the cytotrophoblast cells have degenerated
  • The intervillous spaces (derived from lacunae) between the chorionic and decidual plate are filled with maternal blood
  • The villous trees grow into the intervillous blood lakes

During the fourth and fifth months

• The decidua forms a number of decidual septa:
  
  • Project into intervillous spaces but do not reach the chorionic plate.
  • Structure:
    
    • Core of maternal tissue
    • Surface is covered by a layer of syncytial cells
    • So maternal blood is separated from fetal tissue of the villi.
• As a result of this septum formation
  
  • The placenta is divided into a number of compartments, or cotyledons.
    
    • Since the decidual septa do not reach the chorionic plate, contact between intervillous spaces in the various cotyledons is maintained.
• Continuous growth of the fetus and expansion of the uterus
  
  • Causes continous growth of the placenta
    
    • Increase in surface area roughly parallels that of the expanding uterus and throughout pregnancy it covers approximately 15 to 30% of the internal surface of the uterus.
  • The increase in thickness of the placenta results from expention of existing villi and is not causing further penetration into maternal tissues.

Full term placenta

• Characteristics:
  
  • Discoid shape
  • Diameter of 15 to 25 cm
  • Approximately 3 cm thick
  • Weighs about 500 to 600 g.
• At birth, it is torn from the uterine wall and, approximately 30 minutes after birth of the child, is expelled from the uterine cavity.
• After birth, when the placenta is viewed from:
  
  • The maternal side
    
    • 15 to 20 slightly bulging areas, the cotyledons, covered by a thin layer of decidua basalis, are clearly recognizable.
    • Grooves between the cotyledons are formed by decidual septa.
  • The fetal surface:
    
    • Covered entirely by the chorionic plate.
    • A number of large arteries and veins, the chorionic vessels, group up toward the umbilical cord.
    • The chorion, in turn, is covered by the amnion.
    • Attachment of the umbilical cord is usually eccentric and occasionally even marginal. Rarely, however, does it insert into the chorionic membranes outside the placenta (velamentous insertion).?????

Circulation of the placenta

• Cotyledons receive their blood through 80 to 100 spiral arteries
  
  • Pierce the decidual plate
  • Enter the intervillous spaces at more or less regular intervals
• The lumen of the spiral artery is narrow, so blood pressure in the intervillous space is high.
  
  • This pressure forces the blood deep into the intervillous spaces and bathes the numerous small villi of the villous tree in oxygenated blood.
  • As the pressure decreases, blood flows back to the endometrial veins.
• Collectively, the intervillous spaces of a mature placenta contain approximately 150 ml of blood, which is replenished about 3 or 4 times per minute.
  
  • This blood moves along the chorionic villi, which have a surface area of 4 to 14 m2.
  • Placental exchange does not take place in all villi
    
    • Only villi that lost some of there coverings:
      
      • degeneration of cytotrophoblast cells
    • And are in contact with syncytial membrane
      
      • The placental membrane, which separates maternal and fetal blood, is initially composed of four layers:
        
        • (a) the endothelial lining of fetal vessels
        • (b) the connective tissue in the villus core
        • (c) the cytotrophoblastic layer
        • (d) the syncytium.
      • From the fourth month on, however, the placental membrane thins, thus greatly increasing the rate of exchange.
      • Sometimes called the placental barrier, the placental membrane is not a true barrier, since many substances pass through it freely.

Because the maternal blood in the intervillous spaces is separated from the fetal blood by a chorionic derivative, the human placenta is considered to be of the hemochorial type.

Hemochorial- type of placenta in which maternal blood comes in direct contact with the chorion)

FUNCTION OF THE PLACENTA

Main functions of the placenta are:

1. Exchange of gaseous products between maternal and fetal bloodstreams
2. Exchange of metabolic products between maternal and fetal bloodstreams
3. Production of hormones.

• Exchange of Gases
  
  • Exchange of Gases, such as oxygen, carbon dioxide, and carbon monoxide, is accomplished by simple diffusion.
    
    • At term, the fetus extracts 20 to 30 ml of oxygen per minute from the maternal circulation and even a short-term interruption of the oxygen supply is fatal to the fetus.
• Exchange of metabolic products
  
  • Exchange of Nutrients and Electrolytes is rapid and increases as pregnancy advances.
    
    • Such as amino acids, free fatty acids, carbohydrates, and vitamins
  • Transmission of Maternal Antibodies Immunological competence begins to develop late in the first trimester, by which time the fetus makes all of the components of complement.
  • Immunoglobulins consist almost entirely of maternal immunoglobulin G (IgG) that begins to be transported from mother to fetus at approximately 14 weeks.
    
    • In this manner, the fetus gains passive immunity against various infectious diseases.
    • Newborns begin to produce their own IgG, but adult levels are not attained until the age of 3 years.
• Hormone Production
  
  • All hormones are synthesized in the syncytial trophoblast.
  • By the end of the fourth month the placenta produces progesterone in sufficient amounts to maintain pregnancy.
  • Placenta also produces increasing amounts of estrogenic hormones, predominantly estriol, until just before the end of pregnancy, when a maximum level is reached.
• These high levels of estrogens stimulate uterine growth and development of the mammary glands.
• • During the first two months of pregnancy, the syncytiotrophoblast also produces human chorionic gonadotropin (hCG), which maintains the corpus luteum.
• (This hormone is excreted by the mother in the urine, and in the early stages of gestation, its presence is used as an indicator of pregnancy)
• • Another hormone produced by the placenta is somatomammotropin (formerly placental lactogen). It is a growth hormone-like substance that gives the fetus priority on maternal blood glucose and makes the mother somewhat diabetogenic. It also promotes breast development for milk production.
• • Hormone production summary:
• human chorionic gonadotropin (hCG), which maintains the corpus luteum.
• progesterone – maintain pregnancy (4th month)
• estrogenic (estriol) - uterine growth and development of the mammary glands
• somatomammotropin - gives the fetus priority on maternal blood glucose
  *

Question 23

Development and anomalies of the umbilical cord

Umbilical Cord Abnormalities:

At birth, the umbilical cord is approximately 2 cm diameter and 50 to 60 cm long.

An extremely long cord - may encircle the neck of the fetus, usually without increased risk.

a short cord - may cause difficulties during delivery by pulling the placenta from its attachment in the uterus.

Normally there are two arteries and one vein in the umbilical cord.

In 0.5% of newborns, however, only one artery is present, and these babies have approximately a 20% chance of having cardiac and other vascular defects.

The missing artery either fails to form (agenesis) or degenerates early in development.

Amniotic Bands:

Occasionally, tears in the amnion result in amniotic bands that may encircle part of the fetus, particularly the limbs and digits.

This may result in:

Amputations

ring constrictions

craniofacial deformations

And more.

Origin of the bands is probably from infection or toxic that involve either the fetus, fetal membranes, or both.

Bands then form the amnion, like scar tissue, constricting fetal structures.

FORMATION OF FETAL MEMBRANES

Formation of the fetal membranes:

• Also known as extraembryonic membranes
  
  • (i.e., amnion, chorion, yolk sac, and allantois)

**********************************************

Overview and opening

Prenatal perod: intrauterine development after fertilization of the ovum by sperm up until delivery

• Fertilization (→Zygote)
• Blastogenesis: first 2 weeks after fertilization
• Embryonic period: until end of 8th week (basis of organs are formed)
• Fetal period: until childbirth (growth and functional maturation of organs)

Week 1 of development:

• Ferrtilization→ Zygote→ Cleavlage (repeated mitotic division)→Blastomere (daugter cell of zygote) →Morula (16 cells)→ Blastocyst (inner and outer mass, cavity)→
  
  • Inner cell mass→ embryo proper: embryoblast
  • Outer cell mass→ trophoblast(which later contributes to the placenta.) ​
• Implantation beggins around day 6

Week 2 of development:

• Blastocyst is partially embedded in the endometrial stroma.
• Trophoblast differentiated into two layers:
  
  • Cytotrophoblast- inner layer of mononucleated cells
    
    • Will produce the primary chorionic villi, by protruding into syncytiotrophoblast
  • Syncytiotrophoblast- outer multinucleated zone without distinct cell boundaries.
    
    • The ​periphery the syncytiotrophoblast forms a syncytium
    • multi-nucleic layer without cell boundaries that arises from the fusion of cytotrophoblast cells
  • Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc
    
    • ​Hypoblast and epiblast
    • Two layers are sandwiched between cavities
      
      • Blastocyst cavity→ The primitive yolk sac
      • The amniotic cavity
        
        • Is hollowed out from the middle of the inner cell mass (epiblast part of embryoblast)
        • Amnioblasts: epiblast cells adjacent to the cytotrophoblast
• ​Day 9:
• Surface epithelium at place of implantation is closed by a fibrin coagulum.
• Lacunar stage:
  
  • Vacuoles appear in the syncytium→ fusion of vacules to form large lacuna

​****************************************

Formation of the fetal membranes: extraembryonic membranes

amnion, chorion, yolk sac, and allantois

• Formation of the Amnionic cavity
  
  • Bilaminar disc: Hypoblast and epiblast
  • Space between cytotrophoblast and epiblast is hollowed out
    
    • Amnioblasts: epiblast cells adjacent to the cytotrophoblast
• Formation of the yolk sac and chorion
  
  • Primative yolk sac
    
    • Proliferation of hypoblast cells→ extend around the blastocyst cavity→ forming the exocoelomic membrane, or Heuser’s membrane: Primative yolk sac
  • Definative yolk sac (secondary) and chorion
    
    • Formation of extraembryonic mesoderm (derived from yolk sac cells) appears between:
      
      • The inner surface of the cytotrophoblast
      • The outer surface of the exocoelomic cavity.
        
        • Loose connective tissue.
    • Large cavities develop in the extraembryonic mesoderm→ causing the mesoderm to split and displacment of primary yolk sac→
      
      • (Outer) extraembryonic somatic mesoderm:
        
        • Lines the cytotrophoblast and amnion
      • (Inner) extraembryonic splanchnic mesoderm:
        
        • The lining covering the yolk sac
    • A new space—the extraembryonic coelom, or chorionic cavity—forms by splitting of the extraembryonic mesoderm into two layers.
      
      • This cavity separates the embryo with its attached amnion and yolk sac from the outer wall of the blastocyst
      • Seperation occurs everywhere except the connecting stalk
    • Formation of the chorionic cavity and its enlargement lead to reduction of the cavity of the primary yolk sac:
      
      • A second wave of migration of hypoblast cells produces a new membrane that migrates out over the inside of the extraembryonic mesoderm (splanchnic) pushing the primary yolk sac in front of it.
        
        • This new layer becomes the endodermal lining of the secondary (definitive) yolk sac.
      • Chorionic cavity continues to enlarge
        
        • Remnants of the primary yold sac persist as exocoelomic cysts
      • The secondary yolk sac or definitive yolk sac: is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• Summary:
  
  • Definative yolk sac:
    
    • Extraembryonic endoderm
    • (Inner) extraembryonic splanchnic mesoderm
  • ​Connecting stalk: ???
    
    • ​​extraembryonic splanchnic mesoderm
  • Amnionic cavity
    
    • Amnioblasts and embryonic disc​
  • Chorionic plate
    
    • Extraembrionic somatic mesoderm,
    • Extraembryonic ectoderm
      
      • Cytotrophoblast
      • Syncytiotrophoblast
• The definitive yolk sac
  
  • Remains a major structure associated with the developing embryo through the 4th week and performs important early functions.
    
    • Extraembryonic mesoderm forming the outer layer of the yolk sac is a major site of hematopoiesis- blood formation
    • primordial germ cells can first be identified in humans in the wall of the yolk sac.
  • After the 4th week, the yolk sac is rapidly overgrown by the developing embryonic disc.
    
    • The yolk sac normally disappears before birth, but on rare occasions it persists in the form of a digestive tract anomaly called Meckel’s diverticulum

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Answer 23

Overview:

Summary: The second week of development is known as the week of the twos…

• The trophoblast differentiates into two layers:
  
  • Cytotophoblast
  • Syncytiotrophoblast.
• The embryoblast forms two layers:
  
  • Epiblast
  • Hypoblast.
• The extraembryonic mesoderm splits into two layers:
  
  • (Outer) extraembryonic somatic mesoderm:
    
    • Lines the cytotrophoblast and amnion
  • (Inner) extraembryonic splanchnic mesoderm:
    
    • The lining covering the yolk sac
• Two cavities
  
  • Amniotic
  • Yolk sac

Outer fetal membrane is called Chorion, inner fetal membrane is called Amnion.

Syncytiotrophoblast – producing the human chorionic gonadotropin (hCG) into the maternal blood – to the kidneys – into the urine.

1. Development of chorionic villi, hemoplacental barrier

Thrid week of development

• Further Development of the Trophoblast
  
  • Day 9: Lacunar stage:
    
    • Vacuoles appear in the syncytium→ fusion of vacules to form large lacuna
  • Days 11 and 12: The lacunae become continuous with the sinusoids (Maternal capillaries, which are contacted and dilated) and maternal blood enters the lacunar system.
• By the beginning of the third week:
  
  • Primary Villi -
    
    • Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by syncytium.
    • Primary villi - Cellular columns of cytotrophoblast with the syncytial covering.
• During further development
  
  • Mesodermal cells penetrate the core of primary villi and grow toward the decidua→
    
    • Secondary villi
      
      • Newly penetrated mesoderm core
      • Cytotrophoblastic layer
      • Syncytial layer
• By the end of the third week
  
  • Mesodermal cells in the core of the villus begin to differentiate into blood cells and small blood vessels→ ​
    
    • forming the villous capillary system
• Tertiary villus or definitive placental villus
  
  • ​The villi after the formation of the villous capillary system
  • Capillaries in tertiary villi make contact with capillaries developing in:
    
    • Mesoderm of the chorionic plate
    • Connecting stalk
    • forming the extraembryonic vascular system
• These vessels, in turn, establish contact with the intraembryonic circulatory system, connecting the placenta and the embryo.
  
  • When the heart begins to beat in the fourth week of development, the villous system is ready to supply the embryo with essential nutrients and oxygen.
• Meanwhile, cytotrophoblastic cells in the villi penetrate progressively into the overlying syncytium until they reach the maternal endometrium.
  
  • They establish contact with similar extensions of neighboring villous stems, forming a thin outer cytotrophoblast shell.
    
    • Gradually surrounds the trophoblast entirely and attaches the chorionic sac firmly to the maternal endometrial tissue.
• Anchoring villi:
  
  • Extend from the mesoderm of the chorionic plate to the cytotrophoblast shell reaching thr decidua basalis
• Branch chorionic villi:
  
  • The villi that grow from the sides of the stem villi (terminal villi??).
  • The branches of the villi are the location where the true exchange of material between the blood of the mother and the embryo takes place.

Placenta

The decidua plate (decidua basalis),

The chorion plate (chorion frondosum)

And the the villi system in-between

Circulation of the placenta

Cotyledons receive their blood through 80 to 100 spiral arteries

Pierce the decidual plate

Enter the intervillous spaces at more or less regular intervals

The lumen of the spiral artery is narrow, so blood pressure in the intervillous space is high.

This pressure forces the blood deep into the intervillous spaces and bathes the numerous small villi of the villous tree in oxygenated blood.

As the pressure decreases, blood flows back to the endometrial veins.

Collectively, the intervillous spaces of a mature placenta contain approximately 150 ml of blood, which is replenished about 3 or 4 times per minute.

This blood moves along the chorionic villi, which have a surface area of 4 to 14 m2.

Placental exchange does not take place in all villi
Only villi that lost some of there coverings:

degeneration of cytotrophoblast cells

And are in contact with syncytial membraneThe placental membrane, which separates maternal and fetal blood, is initially composed of four layers:

(a) the endothelial lining of fetal vessels
(b) the connective tissue in the villus core
(c) the cytotrophoblastic layer
(d) the syncytium.

From the fourth month on, however, the placental membrane thins, thus greatly increasing the rate of exchange.

Sometimes called the placental barrier, the placental membrane is not a true barrier, since many substances pass through it freely.

Because the maternal blood in the intervillous spaces is separated from the fetal blood by a chorionic derivative, the human placenta is considered to be of the hemochorial type.

Hemochorial- type of placenta in which maternal blood comes in direct contact with the chorion)

Maternal blood is delivered to the placenta by spiral arteries in the uterus. Erosion of these maternal vessels to release blood into intervilllous spaces is accomplished by endovascular invasion by cytotrophoblast cellsà

These cells, released from the ends of anchoring villi, invade the terminal ends of spiral arteries, where they replace maternal endothelial cells in the vessels walls, creating vessels containing both fetal and maternal cells. To accomplish this process, cytotrophoblast cells undergo epithelial to endothelial transition.

During the following months, numerous small extensions grow out from existing stem villi and extend as free villi into the surrounding intervillous spaces (lacunar spaces). The syncytium and endothelial wall of the blood vessels are then the only layers that separate the maternal and fetal circulations.

By the end of the 3rd week, embryonic blood begins to flow slowly through the capillaries in the chorionic villi.

Oxygen and nutrients in the maternal blood in the intervillous space diffuse through the walls of the villi and enter the embryo’s blood

Carbon dioxide and waste products diffuse from blood in the fetal capillaries through the wall of the villi into the maternal blood.

Villi that attach to the maternal tissues through the cytotrophoblastic shell are called stem chorionic villi (anchoring villi).

The villi that grow from the sides of the stem villi are called branch chorionic villi (terminal villi). It is through the walls of the branch villi that the main exchange of material between the blood of the mother and the embryo takes place.

The branch villi are bathed in continually changing maternal blood in the intervillous space

• decidual plate: the part of the endometrium where the placenta will form
• • Those that branch from the sides of stem villi are free (terminal) villi, through which exchange of nutrients and other factors will occur.
• • The chorionic cavity, becomes larger, and by the 19th or 20th day, the embryo is attached to its trophoblastic shell by a narrow connecting stalk.
• The connecting stalk later develops into the umbilical cord, which forms the connection between placenta and embryo.

Chorionic plate - consist of:

extraembrionic somatic mesoderm

cytotrophoblast

syncytiotrophoblast

• Meanwhile, cytotrophoblastic cells in the villi penetrate progressively into the overlying syncytium until they reach the maternal endometrium.
  
  • Here they establish contact with similar extensions of neighboring villous stems, forming a thin outer cytotrophoblast shell.
  • This shell gradually surrounds the trophoblast entirely and attaches the chorionic sac firmly to the maternal endometrial tissue. Villi that extend from the chorionic plate to the decidua basalis are called stem or anchoring villi.

decidual plate: the part of the endometrium where the placenta will form

Those that branch from the sides of stem villi are free (terminal) villi, through which exchange of nutrients and other factors will occur.

The chorionic cavity, becomes larger, and by the 19th or 20th day, the embryo is attached to its trophoblastic shell by a narrow connecting stalk.

The connecting stalk later develops into the umbilical cord, which forms the connection between placenta and embryo.

→

• • The endometrial stroma adjacent to the implantation site is edematous and highly vascular.
    
    • The large, tortuous glands secrete abundant glycogen and mucus.
    • The uterine glands synthesize or transport and secrete substances essential for survival and development of the embryo or fetus and associated extraembryonic membranes.

​Days 11 and 12

• • The lacunae become continuous with the sinusoids (Maternal capillaries, which are contacted and dilated) and maternal blood enters the lacunar system.
    
    • Uteroplacental circulation -
      
      • As the trophoblast continues to erode more and more sinusoids, maternal blood begins to flow through the trophoblastic system, establishing the uteroplacental circulation.

Day 13

• Occasionally, bleeding occurs at the implantation site as a result of increased blood flow into the lacunar spaces.
  
  • Because this bleeding occurs near the 28th day of the menstrual cycle, it may be confused with normal menstrual bleeding and, therefore, cause inaccuracy in determining the expected delivery date.
• Trophoblast development:
  
  • Is characterized by villous structures.
  • Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, forming cellular columns surrounded by syncytium.
  • Primary villi - Cellular columns of cytotrophoblast with the syncytial covering.
• Embryoblast development
  
  • Formation of the extraembryonic coelom and its enlargement lead to reduction of the cavity of the primary yolk sac (forming the secondary yolk sac).
  • Endodermal cells (yellow) proliferate along the inner surface of exocoelomic membrane and form the wall of the secondary YS. Remnants of the exocoelomic cavity persist as exocoelomic cysts
    • = secondary yolk sac or definitive yolk sac.
      
      • This yolk sac is much smaller than the original exocoelomic cavity, or primitive yolk sac.
• During its formation, large portions of the exocoelomic cavity are pinched off. These portions are represented by exocoelomic cysts, which are often found in the extraembryonic coelom or chorionic cavity.
• Meanwhile, the extraembryonic coelom expands and forms a large cavity, the chorionic cavity.
• The extraembryonic mesoderm lining the inside of the cytotrophoblast is then known as the chorionic plate.
• The only place where extraembryonic mesoderm traverses across the chorionic cavity is in the connecting stalk.
• With development of blood vessels, the stalk becomes the umbilical cord. –

The outer wall of the blastocyst is now called the chorion.

• Inner cell mass (embryoblast) also differentiate into two layers forming a flat bilaminar disc:
  
  • FGF: fibroblast growth factor
    
    • Hypoblast layer -
      
      • a layer of small cuboidal cells adjacent to the blastocyst cavity.
    • Epiblast layer -
      
      • a layer of high columnar cells adjacent to the amniotic cavity.