FDN2_SM_WK4_EmbryologyPatternsDefects Flashcards
What is the most common site of normal implantation?
Posterior wall of the uterus
What are some common sites of ectopic pregnancy?
Uterine tubule, cervix, abdominal cavity, ovary, etc
What are the major events of week 1 of embryogenesis?
Ovulation, conception, migration down the uterine tubule
Where does fertilization usually occur?
The distal 1/3 of the uterine tubule
What are the major events of week 2 of embryogenesis?
Implantation, extra-embryonic membrane formation
What stage is the conceptus when it implants?
Blastocyst
What are the components of a blastocyst?
Trophoblast = outer shell
Inner cell mass
What is the fate of the trophoblast?
It will:
- Differentiate into the outer syncytiotrophoblast and inner cytotrophoblast, then acquire its extraembryonic mesoderm layer (so the cytotrophoblast is now in the middle)
- When it has all 3 layers, it is called the chorion
- The villous chorion invade the endometrium and form the fetal components of the placenta
- The smooth chorion covers the amnion
How does the amnionic cavity form?
The blastocyst hollows to form two layers: The epiblast and the hypoblast
What is #1 pointing to?
Syncytiotrophoblast
What is #2 pointing to?
Amniotic Cavity
What is #3 pointing to?
Ectodermal amnion
What is #4 pointing to?
Epiblast/Ectoderm
What is #5 pointing to?
Hypoblast/Endoderm
What is #6 pointing to?
Trophobolast
The structure labeled by which number will eventually be in direct contact with maternal blood?
1 - the synytiotrophoblast
This layer will form the outermost part of the villious chorion that invades the endometrium and forms the fetal component of the placenta. It will be in direct contact with maternal blood from decidua basalis.
Name the 4 extra-embryonic membranes and their functions
Chorion: Villous forms the placenta, cmooth covers the amnion
Amnion: Surroudns embryo, will eventually fold down to form the cylinder
Yolk Sac: Provides early nutrition. Will become the first source of embryonic blood cells
Alantois: Vestigal membrane in humans
*Yolk Sac + Alantois become the umbilial cord
What is the final step in the formation of the 3 major extraembryonic membranes?
Extraembryonic mesoderm coats the old blastocyst cavity. Everything gets an “extra layer”
Trophoblast -> Chorion
Primary Yolk Sac -> Yolk Sac
Primary Amnion -> Amnion
Which embryonic structure forms the placenta?
The chorion (which came from the trophoblast)
Which embryonic structure forms the umbilical cord?
The yolk sac and the alantois
Which embryonic structure(s) form(s) the afterbirth?
The villous chorion (placenta) and the cytotrophoblastic shell
What is the major event of week 3 of embryogenesis?
Gastrulation (and subsequent formation of the intraembryonic mesoderm)
Describe the formation of the intraembryonic mesoderm
Induced by the primitive knot/node, which forms the primitive streak
Epiblast cells migrate through the invaginating primitive streak to first migrate into the hypoblast (creating a layer of endoderm), then create a layer of mesoderm in between the endoderm and ectoderm
From where does the intraembryonic mesoderm originate?
The primitive streak (epiblast cells migrate through it)
Describe the organization of the mesoderm
Middle = Notochord (induces neural tube)
Paraxial Mesoderm/Column (lateral to notochord)
Intermediate Mesoderm/column (lateral to paraxial)
Most lateral = Lateral Plate
What is the fate of the notochord?
Induces the neural plate (which will become the neural tube)
The notochord itself becomes the nucleus pulposis, the gelatinous interior of vertebral discs
What is the fate of the paraxial mesoderm?
The paraxial mesoderm forms somites, which eventually become bone, muscle, and dermis
What is the fate of the intermediate mesoderm?
The intermediate mesoderm becomes the urogenital system (kidneys and gonads)
What is the fate of the lateral plate mesoderm?
The lateral plate mesoderm contributes to the splanchnopleure and the somatopleure
Splanchnopleure = endoderm + mesoderm from lateral plate -> Walls of gut tube, visceral pleruae, supporting mesenteries (suspend sheets of visceral peritoneum)
Somatopleure = ectoderm + mesoderm from lateral plate-> Lateral and ventral body wall, parietal pleura, parietal peritoneum
Lateral plate + cardiogenic plate -> heart
What is the major event in week 4 of embryogenesis?
Shaping of the gastrula: Turning the trilaminar disk into a cylinder
How does the neural plate form?
Induced by the notochord; thickened ectoderm
What forms the neural tube?
Ectoderm is induced by the notochord to form the neural plate. The neural plate folds in to form the neural tube
What does the neural tube become?
Most of the central nervous system; all cell bodies in the CNS are derived from the neural tube
What forms the neural crest?
Cells break off from the neural crest during neural tube formation; these are neural crest cells
What does the neural crest become?
The peripheral nervous system: all cell bodies in the PNS came from the neural crest
(Dorsal root ganglia, collateral ganglia, sympathetic chain ganglia, post-synaptic autonomic cell bodies)
What 3 parts do somites differentiate into?
What do they become?
Myotome -> Muscle
Dermatome -> Skin/surface ectoderm
Sclerotome -> Bone
Describe the formation of the intra-embryonic celom
Lateral plate mesoderm and cardiogenic mesoderm form a U-shaped tube in the trilaminar disk.
When the disk turns into a cylinder, this becomes the intra-embryonic coelom
Eventually, this will divide into the pleural cavity, pericardial cavity, and peritoneal cavity
What is the origin of the primitive knot/primitive streak?
Appears in the epiblast/ectoderm to initiate gastrulation
What is the origin of the cardiogenic plate?
The cardiogenic plate is derived from splanchnopleuric mesoderm
Which embryonic structure forms the somite?
Paraxial mesoderm/columns
Which embryonic structure forms the urogenital system?
Intermediate mesoderm/columns
Which adult tissues are derived from the surface ectoderm?
Skin, hair, nails
Lining fo mouth, anal canal, GI tract
Think: most things in contact with the outside world (technically, the most luminal cells in the GI tract are continuous with the outside surface of the body)
Where does amniotic fluid come from?
Early: diffusion from maternal tissues + contriubtion from amniotic cells and the embryo
Later: When the urogenital system forms, the amniotic fluid is mostly fetal urine that the fetus swallows and recycles
What is the function of amniotic fluid?
Protect the fetus, allow for movement
What conditions can result in polyhydroaminos?
Polyhydroaminos = too much amniotic fluid
Causes: inhibition of swallowing (anecephaly) or absorption (transesophageal fistula)
What conditions result in too little amniotic fluid?
Renal agenesis (newborn is missing one or both kidneys)
Other conditions resulting in lack of kidney function/urine production
Describe the structure of the placenta
All 3 layers of the chorion (which came from the trophoblast) form a finger-like projection (villous) that invades the endometrium.
The villous chorion has the outer syncytiotrophoblast, the extra-embryonic mesenchyme conenctive tissue core (blood vessels), and the cytotrophoblast in between them. The cytotrophoblast eventually disappears.
The decidua basalis of the endometrium is basically an open blood vessel that bathes the villous chorion in maternal blood.
What is the structure labeled #1?
The amnion
What is the structure labeled #2?
The splanchnopleure
What is the structure labeled #3?
The somatopleure
What is the space labled #4?
The intraembryonic coelom
What is the space labeled #5?
The gut tube
What is the yellow layer in this picture?
The endoderm
What is the cloacal membrane?
A membrane present at the posterior end of the embryo after gastrulation
It will eventually form the anus
When do the cloacal and oral membranes arise?
After gastrulation
What is mesenchyme?
Loose connective tissue in the mesoderm
Mesenchyme gives rise to most of the body’s connective tissue
What is the source of blood vessels in placenal villus?
Extraembryonic Mesoderm
What is the source of cardiogenic mesoderm?
Primitive streak
What gives rise to the chorion?
Trophoblast
When is the embryonic period?
2-8 weeks (biological)
What is the difference between biological age and clinical age of an embryo?
Biological age = Starts at fertilization of the egg
Clinical age/gestational age= Starts with the first day of the last normal menstrual period (add 2 weeks to biological time). This is used because the exact day of fertilization is usualy not known
Which embryonic structure forms the vertebrae?
The paraxial mesoderm (vertebrae come from somites, which come from paraxial mesoderm)
When does patterning occur in human development?
In weeks 4-8
What is the end of week 8 a significant time point in embryonic develpment?
At the end of week 8, all of the organs are formed and axes are established. The embryo is now a fetus (anything later than week 8 is the fetal period)
Which mechanism establishes the anterior/posterior axis in the embryo?
HOX genes
Describe the organization of the HOX gene complex
HOX genes with lower numbers are at the 3’ end of the chromosome, while genes with higher numbers are at the 5’ end
Describe temporal colinearity of HOX genes
Genes at the 3’ end of the complex (lower numbers) are expressed earlier in development
Genes at the 5’ end of the complex (higher numbers) are expressed later in development
Describe spatial colinearity of HOX genes
Genes at the 3’ end of the HOX complex (lower numbers) have expression that extends more anteriorly
Genes at the 5’ end of the HOX complex (higher numbers) have expression that ends more posteriorly
Describe posterior prevalence
More HOX genes are expressed in posterior regions (Lots of overlap posteriorly)
Describe posterior dominance
If several HOX genes are expressed in a segment, the one whose expression ends furthest poteriorly determines the segment phenotype
For example: In the segment underlined in blue, HOX-B5 determines the phenotype for that segment
(HOX-B4 and HOX-B3 have expression that ends more anteriorly, so they do not determine the segement phenotype)
What is a homeotic gene?
Any gene that determines the fate or identity of body segments
Describe redundancy in HOX genes
There is considerable redundancy in function between paralogous HOX genes in different complexes
Ex: HOX-A4 = HOX-B4 = HOX-C4 = HOX-D4
Where do HOX genes exhibit colinear expression?
Along the primary anterior/posterior axis
Along regional/organ-specific axes (limbs, GI tract, female reproductive tract)
Which protein establishes the dorsal/ventral axis in the central nervous system and somites?
Sonic Hedgehog (Shh)
Describe the Shh signaling pathway
- The Shh receptor is Patched (Ptc)
- If no Shh, Ptc inhibits the signaling pathway
- When Shh binds to patched, the pathway is activated
- The signaling pathway activates the GLI family of transcription factors
- GLI1 = transcription activator
- GLI2 = transcription activator or repressor
- GLI3 = transcription repressor
What is an organizing (aka patterning) center?
A region that secretes Shh
Name 2 organizing centers in human embryos
- Notochord
- Zone of Polarizing Activity
Which axes are established by Shh signaling?
- Dorsal/Ventral axis in CNS and somites
- Anterior/posterior axis in developing limbs
Which axis is established by HOX gene signaling?
Anterior/Posterior
Hox genes determine the fate or identity of body segments along the anterior/posterior axis
Describe Shh signaling of dorsal diffusion from the notochord
Establishes Dorsal/Ventral axis in CNS
- Shh is secreted from the notochord -> Dorsal diffusion
- High concentration -> induces neural tube
- Low concentration -> induces sensory ganglia/neurons (from the neural crest)
Describe Shh signaling of lateral diffusion from the notochord
Establishes Dorsal/Ventral axis in Somites
- Shh is secreted from the notochord -> Lateral diffusion
- High concentration (ventral-medial somites) -> Sclerotome -> vertebral bodies, ribs
- Low concentration (dorsal-lateral somites) -> Dermomyotome -> Dermis, musculature
Describe Shh signaling right above the notochord
Highest concentration:
Induces the ventral floor plate, motor neurons in the ventral neural tube
Describe Shh signaling in developing limbs
Shh is secreted from the Zone of Polarizing Activity in the proximal-posterior aspect of the limb bud
- High concentration -> 5th digit/posterior side
- Low concentration -> 1st digit/anterior side
In a limb bud, high concentrations of Shh induce the ________ side
5th digit/posterior
(Recall that the ZPA is in the proximal-posterior aspect of the limb bud)
Where is the Zone of Polarizing Activity (ZPA) located in the limb bud?
The proximal-posterior aspect of the limb bud
What mutation results in synpolydactyly?
HOX-D13
Describe the effect of a HOX-D13 mutation
Synpolydactyly (distal metacarpals take on a more proximal/carpal phenotype)
Heterozygotes: “branching”
Homozygous for the mutated allele: All metacarpals have a carpal phenotype
What mutation results in holoprosencephaly?
Shh LOF
The signaling pathway is never activated since Shh cannot bind to Ptc to remove pathway inhibition
Describe the phenotypic result of an Shh LOF mutation
Holoprosencephaly
This is the result of abnormal septation of the hemispheres of the brain and resultant anormal CNS patterning
In this LOF mutaiton, Shh cannot inacivate Ptc to turn on the signalling pathway
(eyes are close together or there is only 1 eye)
What mutation results in Basal Cell Nevus Syndrome?
Patched1 inactivation
This results in constitutive signaling pathway activation
Describe the phenotypic result of a Patched1 mutation
A mutation in Ptc results in constitutive activation of the Shh signaling pathway
The result of a Patched1 mutation is Basal Cell Nevus Syndrome, characterized by large head, wide-spaced eyes, rib and abdomen abnormalities, and a predisposition to cancer
What mutation causes cephalopolysyndactyly?
GLI3 Mutation
Normally, when GLI3 is activated itrepresses transcription
A GLI3 mutation results in abnormal activation, which results in extra fingers
Describe the phenotypic result of a GLI3 mutation
Cephalopolysyndactyly (aka polydactyly)
Extra fingers or toes
What is the difference between a transgenic mouse and a knockout mouse?
Trangenes: expressed at the wrong time or wrong place during development
Knockout: The functional gene or protein is removed
What is the expected phenotype with inapproporate loss of expression of a HOX gene?
The segment in which expression is lost will have a more anterior phenotype than normal
What is the expected phenotype wiht inappropriate ectopic anterior expression of a HOX gene?
The segment with ectopic anterior expression will have a more posterior phenotype than normal
What characteristic defines a tissue with organizing properties?
It affects the development of neighboring regions
What is the fate of the lateral dermomyotome?
Lateral dermatome -> skin of ventral wall, limb
Lateral myotome -> Muscle of ventral wall, limb
What is the fate of the medial dermomyotome?
Medial Dermatome -> Skin of back
Medial Myotome -> Muscle of back
What is the fate of teh sclerotome?
Vertebral bodies, ribs
Monozygotic twins have share ________ and have their own ______
Share: Chorion, Placenta
Have their own: Amnion, yolk sac
(So there will be 1 chorion, 1 placenta, 2 amnions, and 2 yolk sacs in a pregnancy of monozygotic twins)
What causes the separation of the pleural and peritoneal cavities?
The septum transversum: A condensation of primitive streak mesenchyme
What is the septum transversum? What does it do?
The septum transversum is a condensation of primitive streak mesenchyme
It separates the pleural and peritoneal coelom
What is a malformation?
Poor formation of tissue due to an intrinsically abnormal developmental process
What is a deformation?
Unusual (mechanical) forces on normal tissue cause abnormal form or position of a body part
What is a disruption?
Breakdown of normal tissue
Describe the timing of a malformation
The gestational age at which the distubance in morphogenesis was caused is between 2-8 weeks
Which of the three types of congenital anomolies are caused during the fetal period?
Deformations and disruptions
The fetus is exposed to the cause of abnormal morphogenesis sometime after 8 weeks
Which of the three types of congenital abnormalities may be spontaneously correted?
Disturbances
Give some examples of malformations
Cleft lip
Polydactyly
Syndactyly
Ectrodactyly
Radial hypoplasia
Spina Bifida
Give some examples of deformations
Club foot
Mandibular asymmetry
Potter’s sequence
Plagiocephaly
Micrognathia
Give some examples of disruptions
Amputated fingers
Amniotic bands
Encephalocele
What are some common causes of deformations?
- Amniotic tear -> oligohydraminos -> compression on the fetus
- Twins
- Unusual implantation site
- Uterine malformaiton
- Malformations (ex: Spina bifida -> renal agenesis -> oligohydraminos)
- Functional causes (muscualr disturbance -> decreased movement -> Deformation)
What are the common causes of malformations?
Single gene
Chromosome abnormality
Multifactorial trait
Maternal influence
Unknown
What is a “sequence?”
Condition in which there are several abnormalities arising as secondary consequences of a single underlying problem
What is a “syndrome?”
Condition in which there are several abnormalities of apparently independent origin
What is the Pierre-Robin Sequence?
Malformation sequence: Mandibular hypoplasia -> failure of tongue descent -> cleft palate
Deformation sequence: Mandibular constraint -> failure of tongue descent -> cleft palate
A minor anomoly is usually of no functional significance to the individual. Why then, are clinicians concerned with identifying them at birth?
When there is one, there is a high probability that there is another that may be major
- Newborns with 3+ minor anomalies have a 90% chance of having a major anomaly
- 42% of patients with idiopathic mental retardation have 3+ anomalies (80% of which are minor)
- Minor anomalies are present in many congenital abnormality syndromes
What is the difference between a teratogen and a mutagen?
A teratogen causes developmental toxicity that can alter viability or a specific organ system
A mutagen induces a change in DNA (at any change in life)
What are the 4 main categories of teratogens?
Maternal factors
Drugs (Chemical Factors)
Infectious Agents (TORCH)
Physical agents (Ionizing Radiation)
What factors affect the dose of a teratogen that reaches the embryo?
Fetal or maternal genotype, other drugs, concomitant disease
What is a teratogen?
A chemical, physical, or infectious agent that affects viability of the embryo or specific organ systems.
Describe specificity, as it relates to teratogens
Each teratogen produces a consistent, specific malformation* at a specific time during development
Ex: Phenytoin -> nail and 5th finger hypoplasia
Valproic acid -> neural tube defect
*To cause its specific malformation, a teratogen must act at 2-8 weeks gestational age
What is the “all or none” period? What is its significance?
0-2 weeks (this is prior to implantation)
At this stage, exposure to a teratogen will kill the embryo
If the embryo doesn’t die, it was probably not exposed
What happens if a developing fetus is exposed to a teratogen during the fetal period?
By definition, a teratogen produces a specific malformation that affects viability of the embryo or specific organ systems.
In the fetal period, teratogens can affect fetal growth, and size and function of a specific organ. However, they will not “act” to cause their characteristic malformation
*Note: I am basing this off of the guiding questions/answers to Charrow’s learning guide. Please let me know if this information is wrong!
What maternal factors can cause teratogenic conditions?
Maternal Diabetes Melitus
Maternal Phenylketonuria (PKU)
How might maternal PKU affect gestation?
If PKU is well managed and phenylalanine levels remain low, there may be no effect
If PKU is not well-managed, fetal exposure to high phenylalanine levels results in malformation in >90% of infants
- Mental retardation
Microcephaly, congenital heart defects
What specific malformations are associated with maternal diabetes melitus?
- Caudal regression syndrome
- Spine/lower extremity malformation
- Congenital heart malformation
- Brain malformation
Note: Effects are more likely if blood glucose is poorly controlled
What physical factors are teratogenic?
Ionizing radiation
(doses used for diagnostic purposes are usually negligible)
What specific malformations are associated with ionizing radiation?
Exposure 2-5 weeks post conception ->
- Intrauterine growth retardation
- CNS damage
- Microcephaly
- Ocular defects
What specific malformations are associated with Warfarin exposure?
Exposure during weeks 6-9 ->
- Nasal Hypoplasia
- Stippling (punctate calcification aka bone dots in cartilage)
- Shortening of distal phalanges, small nails
- Intrauterine growth retardation
- Deafness
- CNS, opthalmologic, cardiac abnormalities
What is the mechanism of action of the teratogenic effects of Warfarin?
Warfarin (and other coumarin derivatives) inhibit vitamin-K dependent clotting factor activation
- They interfere with the gamma-carboxylation step, which eventually results in deficient arylsulfatase E
This results in the characteristic phenotype (small nose, stippling)
What are the common teratogenic infectious agents?
TORCH
- T = Toxoplasmosis
- O = Syphillis
- R = Rubella
- C = Cytomegalovirus
- H = Herpes
What is a critical period?
The time during gestation when the development of a specific organ can be altered
