Early Fetal Development Flashcards
What are the 3 ways to measure embryo-fetal development time?
Embryo-fetal developmental progression can be measured in different ways:
- Fertilization age (conceptual age) = measured from the time of fertilisation (assumed to be +1 day from last ovulation)
- Gestational age: calculated from start of last period (day 0), and ovulation happens 14 days after this
- Carnegie stage: based on presence or absence of certain embryo features
Why is fertilisation age not very practical?
Usually a period of time has elapsed after fertilisation so days/ weeks post fertilisation, this is v difficult to know in practice
Variaiblity in time between intercourse and fertilisation in natural conception
Can be inferred if we know time of ovulation
Only can know exact time if using IVF
What is gestational age?
Calculated from the time of the beginning of the last menstrual period (LMP)
Determined by fertilization date (+14 days) if known, or early obstetric ultrasound and comparison to embryo size charts
What is carnegie stage?
Based on embryo features rather than time
23 stages of embryo development based on embryo features not time
Allows comparison of developmental rates between species
Covers the window of 0-60 days fertilization age in humans
What are the 3 stages of pregnancy?
Embryogenic stage
Embryonic stage
Fetal stage
What is the Embryogenic Stage?
14-16 days post-fertilization - part of first trimester
Form early embryo from fertilised oocyte and formation of 2 cell types:
Pluripotent embryonic cells (contribute to organs of fetus)
Extraembryonic cells (contribute to the support structures e.g. placenta)
What is the Embryonic Stage?
16-50 days post fertilisation - part of first trimester
Establishment of germ layers, differentiation of tissue types, and body plan - major organ systems are specified
What is the Fetal Stage?
50-270 days post-fertilisation (8-38 weeks) - so transition from embryo to fetus occurs roughly at end of first trimester, and fetal stage makes up the 2nd and 3rd trimesters
Major organ systems now present but these are now migrating to their final location
Extensive growth and acquisition of fetal viability - ability of foetus to survive outside the womb
What is the developmental trajectory for the first few days of life?
Ovulated oocyte after fertilisation = zygote
Zygote undergoes mitotic division (cleavage) = 2 cell embryo to 4 cell embryo to 8 cell embryo (these are cleavage stage embryos)
8 cell embryo proceeds with further mitotic divisions to form a morula (16 cell)
Morula forms an blastocyte (around day 5)
This developmental trajectory is happening as the oocyte/ early embryo is travelling along the fallopian tube and into the uterus to be implanted
The zona pellucida (hard, protein shell) that surrounds the oocyte at ovulation is present at all these stages so all these mitotic divisions are happening within the constriction of the ZP
What is the first major developmental event?
Maternal-to-Zygotic transition
What is the Maternal-to-Zygotic transition?
Occurs at the 4-8 cell stage
We start to get transcription of embryonic genes and lose the reliance on maternal mRNA and proteins - i.e. embryotic genes take over and begin transcription
Embryo increases protein synthesis and organelle (mitochondria, Golgi) maturation
How does the cell divide prior to Maternal-to-Zygotic transition?
No genes are transcribes
Divisions dependent on maternal mRNA and proteins
What is the second major developmental event?
Compaction
What happens during Compaction?
Early events (compaction and blastocyst formation) separate the embryo into embryonic (inner cell mass) and extra-embryonic cells (trophectoderm)
Compaction occurs at the 8 cell stage
Gives us our first 2 cell lineages (2 distinct cell types):
- Outer cells: tightly bound wedge-shaped outer cells (green)
As outer cells become pressed against zona they change from spherical to wedge-shaped.
- Inner cells: shielded from outside (pink)
Outer cells become polarised and connect to each other through tight gap junctions and desmosomes = to form barrier to diffusion between cells inside the embryo and the outside of the embryo
What is the third major developmental stage?
Blastocyte formation stage - establishes the 2 cell types
How do the 2 types of cells formed in the Compaction stage develop further in the Blastocyte formation stage?
These 2 cells types develop further:
Outer cells form outer shell of blastocysts
Inner cells clumping together at one end and there is formation of the blastocoel cavity
Once this happens the morula is a blastocyst
What is the zona pellucida and why is it important?
Hard protein shell inhibiting polyspermy (multiple sperm fertilisation) and protecting the early embryo
What is the purpose of the inner cell mass at the blastocyte formation stage?
Gives rise to the pluripotent embryonic cells that will contribute to the final organism
What is the purpose of the outer cell mass at the blastocyte formation stage?
AKA the Trophoectoderm/ trophoblast:
Give rise to extra-embryonic cells that contribute to the extraembryonic structures that support development e.g. placenta
What is the formation of the Blastocoel at the blastocyte formation stage?
Fluid-filled cavity formed osmotically
Trophoblasts pump Na+ ions into centre of the embryo, and water follows this osmotically to form large fluid-filled space in middle
What is hatching and why is it important?
Escape of the blastocyst from the zona pellucida shell - around day 5-6
Essential for further development and implantation (into endometrium)
How does hatching occur?
Blastocyst secretes enzymes = enzymatic digestion
And cellular contractions of the embryo
Both contribute to weaken zona pellucida
Once the embryo has implanted into the endometrium, it undergoes peri-implantation events.
What are the peri-implantation events?
Further differentiation of the embryo - 7-9 days post fertilisation
- Trophectoderm lineage separates
- Inner cell mass separates
What does the trophectoderm lineage separate to?
Trophectoderm lineage separates into the syncitiotrophoblast and the cytotrophoblast
The trophoblast cells fuse to form syncitiotrophoblast, which is invasive - invades uterine endometrium and starts to degrade endometrium cells to breakdown capillaries = allows syncitiotrophoblasts to bathe in maternal blood
This creates interface between embryo and maternal blood supply
Cytotrophoblast cells remain individual cells and contrinue to divide (proliferate) to add cells to the syncitiotrophoblast cells
What does the inner cell mass separate to?
Epiblast and hypoblast
Epiblast = from which the fetal tissues and organs will be derived
Hypoblast = which will form the yolk sac (extraembryonic structure important in gut development + early haematopoesis), this lines the under-side of the epiblast and faces the cavity
What is the final developmental stage?
Occurs around day 12
Formation of the bilaminar (two-layer) embryonic disc is the final stage before gastrulation
At this stage:
Syncitiotrophoblast continues to expand into the endometrium to firmly implant embryo in endometrium and begin secreting hCG
Some of the epiblast cells become separated from the main block of epiblasts by the formation of a new cavity – the amniotic cavity.
The epiblast cells at the top of the amniotic cavity give rise to the amnion and these amnion cells will contribute to the extra-embryonic membranes
The epiblast cells below the amniotic cavity will be the ones that give rise to the fetal tissue structures and organs
There is a layer of hypoblast below the epiblasts which faces the blastocoel, together they form a bilaminar embryonic disc
At this stage it is ready for gastrulation
What forms the basis of pregnancy testing?
Detection of beta hCG subunit in blood/urine is basis of pregnancy testing
What is gastrulation?
The process whereby the bilaminar embryonic disc undergoes reorganisation to form a trilaminar disc:
Ectoderm (upper)
Mesoderm
Definitive endoderm
What happens during the third week of development?
The bilaminar embryonic disc differentiaties to establish three primary germ layers = this is called gastrulation
What happens during the primitive streak formation in gastrulation?
What is the purpose of the primitive streak?
Occurs around 15 days after fertilisation
A thickened structure forms along the midline of the epiblasts on the upper surface called the primitive streak from the caudal end of the bilaminar embryonic disc
Formation of the primitive streak defines head / cranial and tail / caudal ends, and the left-right axes of embryo
What occurs to the primitive streak at the cranial end of the embryonic disc?
Primitive streak expands to form a primitive node
This contains a circular depression - primitive pit
What happens to the primitive pit?
This depression continues along the midline of the epiblasts, towards the caudal end
Forms the primitive groove
So what makes up the primitive streak?
The primitive groove + primitive pit + primitive node = primitive streak
What is invagination?
Cells of the epiblast migrate inwards towards the primitive streak and dive into the primitive groove
They detach from the epiblast
And lip beneath it into the interior of the embryo
What do the first invaginated cells do?
The first cells to invaginate through the primitive groove invade the hypoblasts and displace its cells and eventually the hypoblast cells are completely displaced by a proximal cell layer (the definitive endoderm)
What happens by day 16?
Majority of hypoblast has been replaced
Remaining cells of the epiblast are referred to as the ectoderm
What does the ectoderm form?
Most exterior, distal layer
What do the other invaginated cells do?
Remain in the space between the ectoderm and definitive endoderm - form a germ layer - the mesoderm
Recap what happens during gastrulation for the formation of the 3 germ layers:
Ectoderm (upper)
Mesoderm
Definitive endoderm
Thickened structure forms along the midline of the epiblasts on the upper surface from the caudal end of the bilaminar embryonic disc = primitive streak
Primitive streak expands, forms primitive node
Primitive node has a depression = primitive pit
Depression continues along the midline of the epiblasts, towards the caudal end = primitive groove
The epiblast cells start to migrate towards primitive groove and dive into it
The epiblast cells that slip through the groove differentiate to form different layers:
- First vaginated cells = definitive embryonic endoderm cells which replace the ventral hypoblast layers
- Form embryonic mesoderm layer
The epiblast cells that don’t dive into the groove are called the embryonic ectoderm layer
What are the properties of the 3 germ layers?
These germ layers are multipotent - they can differentiate into any tissue or organ
What organs are formed by the ectoderm?
CNS and neural tract
Skin epithelia
Tooth enamel
What organs are formed by the mesoderm?
Blood (endothelial cells, red and white blood cells)
Muscle (smooth, skeletal and cardiac)
Gonads, kidneys and adrenal cortex
Bone, cartilage
What organs are formed by the endoderm?
GI tract
Liver, pancreas
Lung
Thyroid
What is the first major event after gastrulation?
Notochord formation at day 13
A rod- like tube structure made of cartilage-like mesoderm cells forms from end of primitive streak and grows forward towards the cranial end of the embryo, along the midline
It grows underneath the ectoderm along the embryo midline.
What is the function of the notochord?
Acts as a key organizing centre for neurulation and mesoderm development
Releases growth factor signals
What is neurulation?
Process of CNS formation
Neural plate is an area of thickened ectoderm that sits on top of the embryo.
Signals from the notochord beneath the ectoderm will move up through the embryo to direct the neural plate to form the neural tube
Neurulation refers to the folding process in which the neural plate bends up and later fuses to form the hollow tube that will eventually differentiate into the brain and the spinal cord of the central nervous
What does the neural plate do?
Around day 15
In order to form CNS, the notochord signals direct the neural plate ectoderm to invaginate forming neural groove
This creates two ridges (neural folds) running along the cranio-caudal axis
Neural crest cells (Ectoderm) specified in neural folds
What happens a few days later, after neural fold formation?
Neural folds move towards each other (up and across) over neural groove
Ultimately the neural folds fuse, forming a hollow tube (neural tube) running across the whole embryo
Neural tube overlaid with epidermis (ectoderm)
Neural crest cells from folds will migrate away - to populate different tissues
What happens to the neural tube?
Neural tube overlaid with epidermis (ectoderm derived)
Initially open at each end as it runs along the length of the embryo, closes at later days
Must close for formation of brain structures
When does the neural tube close at the head end?
When does the neural tube close at the tail end?
Day 23
Day 27
What conditions are caused by failure of neural tube closure?
Failure of neural tube closure = common developmental defect
Anencephaly - (absence of most of the skull and brain) arises from failure to close at the head end (1/10,000 births)
Spina bifida - (open neural tube at birth, usually lower spine due to failure to close tail end– varying severity – (0.4-5/1000 births)
What are the features of neural crest cells?
Endoderm derived
Highly plastic and migrate extensively during development
Give rise to a variety of cell types
How are neural crest cells classified?
By where they end up in the embryo
What are the different neural crest cells?
Cranial NC = cranial neurones, glia, lower jaw, middle ear bones (ossicles), facial cartilage
Cardiac NC = aortic arch/pulmonary artery septum, large arteries wall musculoconnective tissue
TrunkNC = dorsal root ganglia, sympathetic ganglia, adrenal medulla, aortic nerve clusters, melanocytes
Vagral and Sacral NC = dorsal root ganglia, sympathetic ganglia, adrenal medulla, aortic nerve clusters, melanocytes
What do defects of neural crest migration/specification lead to?
Diverse birth defects including: Pigmentation disorders Deafness Cardiac defects Facial defects Failure to innervate the gut
What is the next key stage after neuralation?
Somitogenesis
What happens during somitogenesis?
Created formation of blocks of medoderm along the axis of the embryo - called somites
On either side of neural tube we have blocks of specialised mesoderm cells called paraxial mesoderm. Blocks of paraxial mesoderm condense and bud off in somite pairs starting from cranial end and progressing to the caudal end.
Rate of ‘budding’ or appearance of somite pairs is species-specific, as is the number of pairs so humans form new pair per 90 minutes and this leads to around 44 pairs in the embryo
What do somite pairs look like on embryo imaging?
Chevron structures
Blocks lining up along the back of the embryo
What 2 types of embryonic tissue do the somites initially give rise to?
- Sclerotome = vertebrae and rib cartilage
- Dermomyotome = sub-divides to form:
Dermatome = dermis of the skin, some fat and connective tissues of neck and trunk
Myotome= muscles of the embryo
From what does the primitive gut arise?
Primitive gut arises around Day 16 from 2 types of folding in the embryo:
Ventral folding = where the head and tail ends curl together
Lateral folding = where the two sides of the embryo roll
These 2 types of embryonic folding pinch off part of the yolk sac to form the primitive gut
What subsequently happens to the primitive gut?
Patterned into foregut, midgut and hindgut
Foregut = esophagus, stomach, upper duodenum, liver, gallbladder, pancreas
Midgut = lower duodenum and remainder of small intestine, ascending colon and first two-thirds of transverse colon
Hindgut = last third of the transverse colon, descending colon, rectum and upper anal canal
What are the features of heart development?
Begins as tube of mesoderm around day 19
By day 22, it is beating and pumping blood
Fetal heartbeat detectable from ~6 weeks gestational age
What are the features of lung development?
Arise from the lung bud (a structure that sits adjacent to the foregut), an endodermal structure, beginning in the 4th week of development
Lung bud splits into two at the end of the 4th week, and progressively branches through development.
What are the features of lung development?
Arise from the lung bud, an endodermal structure that sits adjacent to the foregut, beginning in the 4th week of development
Lung bud splits into two at the end of the 4th week, and progressively branches through development (gives rise to the bronchi and bronchioles)
What do the gonads form from?
Gonads are mesodermal derived structures
Initially they are bipotential (i.e. not committed to the testes or ovaries) = 2 thickenings of mesoderm towards the caudal end known as the gonadal ridges
In XY embryos, presence of SRY gene on Y chromosome directs gonadal cells to become Sertoli cells, triggering testis development, Leydig cell formation and testosterone production therefore masculinisation of embryos
In XX embryos, absence of SRY leads to gonadal cells adopting a granulosa cell fate and ovary development, requires reinforcement by FOXL2 (transcription factors) essential for ovary development
