10.2 - Early Foetal Development

Question 1

What is fertilisation age (aka conceptual age) of a foetus?

Answer 1

• time measured from time of fertilisation (assumed to be +1 day from last ovulation)
• not particularly useful, but widely used
• difficult to know time of fertilisation exactly (unless IVF)

Question 2

What is gestational age of a foetus?

Answer 2

• calculated from the time of the beginning of the last menstrual period (LMP)
• ovulation occurs 14 days into menstrual cycle and if fertilised, it signals corpus luteum to make progesterone to maintain endometrial lining
• determined by fertilisation date (+14 days) if known, or early obstetric ultrasound and comparison to embryo size charts

Question 3

What is Carnegie staging system?

Answer 3

• 23 stages of embryo development based on embryo features not time
• covers the window of 0-60 days fertilisation age in humans
• allows comparison of developmental rates between species

Question 4

What three stages can we split pregnancy into based on foetal development?

Answer 4

• embryogenic stage
• embryonic stage
• foetal stage
• first trimester - embryogenic and embryonic stages
• second and third trimester - foetal stage
• transition from embryo to foetus is at the end of the first trimester going into the second

Question 5

What is the embryogenic stage?

Answer 5

• 14-16 days post-fertilisation
• establishing the early embryo from the fertilised oocyte
• results in formation of two cell types:
• pluripotent embryonic cells - contribute to foetus
• extraembryonic cells - contribute to support structures e.g. placenta

Question 6

What happens in the embryonic stage?

Answer 6

• 16-50 days post fertilisation
• establishment of germ layers and differentiation of tissue types
• establishment of the body plan

Question 7

What is the foetal stage?

Answer 7

• 8 to 38 weeks
• major organ systems now present
• migration of some organs to final location
• extensive growth and acquisition of foetal viability (survival outside the womb)

Question 8

What stages of development does the oocyte/zygote go through in the first few days of life?

Answer 8

1. ovulated oocyte (1 cell)
2. fertilisation –> zygote (1 cell)
3. cleavage stage embryos - cell divides in 2 –> 4 –> 8
4. morula (16+ cells)
5. blastocyst (200-300 cells) - load of cells accumulate at one end, some surround edges, fluid centre

• occurs in the confines of the zona pellucida as the embryo moves down Fallopian tube into uterus
• only implanted in uterus after blastocyst formation

Question 9

Describe the first major embryonic developmental event - maternal-to-zygotic transition

Answer 9

• until 4-8 cell stage, genes of the embryo are not transcribed
• embryo is dependent on maternal mRNAs and proteins to get through the first divisions
• these mRNAs and proteins are synthesised and stored during oocyte development (i.e. pre-ovulation)
• in maternal-to-zygote transition, there is transcription of embryonic genes (zygotic genome activation), increased protein synthesis, and organelle (mitochondria, Golgi) maturation
• failure to synthesise, store or interpret these mRNAs and proteins during oogenesis can impair embryonic development

Question 10

Describe the second major embryonic developmental event - compaction

Answer 10

• around 8 cell stage or later, outer cells in embryo become pressed against zona pellucida and change from spherical to wedge-shaped
• they connect to each other through tight gap junctions and desmosomes
• this forms a barrier to diffusion between inner and outer embryo
• outer cells often becomes polarised
• forms a compacted morula with two distinct cell populations - inner cells shielded from external environment, and outer cells exposed
• these then develop to form a blastocyst with the formation of a blastocoel cavity

Question 11

What are the four different layers of the blastocyst?

Answer 11

• zona pellucida - hard protein shell inhibiting polyspermy and protects early embryo
• inner cell mass - pluripotent embryonic cells that will contribute to the final organism
• trophoectoderm - extra-embryonic cells that contribute to the extraembryonic structures that support development e.g. placenta (surround inside)
• blastocoel - fluid-filled cavity formed osmotically by trophoblast pumping Na+ ions into the centre of the embryo, which water follows

Question 12

What is hatching and why is it important?

Answer 12

• to implant the blastocyst, it must escape the zona pellucida
• hatching - day 5-6
• through enzymatic digestion (enzymes secreted by blastocyst) and cellular contractions, a point of the zona pellucida is weakened and the blastocyst extrudes out of the zona shell

Question 13

What happens to the trophectoderm lineage peri-implantation (day 7-9 after embryo has made first contact with endometrium)?

Answer 13

• trophectoderm lineage separates further into a syncitiotrophoblast and cytotrophoblast
• syncitiotrophoblast invades uterine endometrium and destroys local maternal cells, and breaks up capillaries to create interface between embryo and maternal blood supply
• cytotrophoblast cells remain individual to divide and provide source of syncitiotrophoblast cells

Question 14

What happens to the inner cell mass peri-implantation (day 7-9 after embryo has made first contact with endometrium)?

Answer 14

• inner cell mass separates further into:
• epiblast - from which the foetal tissues will be derived
• hypoblast - which will form the yolk sac (extraembryonic structure)

Question 15

What happens on day 12 after fertilisation?

Answer 15

• bi-laminar embryonic disc formation - final stage before gastrulation
• some epiblast cells become separated from the rest of them by the formation of an amniotic cavity
• these amnion cells will contribute to the extra-embryonic membranes
• this leaves a two-layer disc of epiblast and hypoblast, sandwiched between cavities (amnions –> amniotic cavity –> epiblast –> hypoblast –> blastocoel)
• epiblast goes on to form foetal structures and organs
• syncitiotrophoblasts start secreting hCG - detection of
  beta-hCG subunit in blood/urine is basis of pregnancy testing
• embryo ready for gastrulation

Question 16

Summary of what happens in pre and peri-implantation development

Answer 16

Embryonic:

• morula –> inner cell mass –> epiblast (–> epiblast + amnion) + hypoblast

Extra-embryonic:

• morula –> trophoblast –> cytotrophoblast + syncitiotrophoblast

Question 17

What is gastrulation?

Answer 17

The process where the bilaminar embryonic disc undergoes reorganisation to form the trilaminar disc

Question 18

What happens 15 days after fertilisation?

Answer 18

• thickened structure forms along midline of epiblast, near caudal end of bilaminar embryonic disc
• this dictates cranial and caudal ends of the embryo

Question 19

What happens to the primitive streak nearer the cranial end?

Answer 19

• expands to create a primitive node
• this contains a circular depression - the primitive pit - which continues along the midline of epiblast towards caudal end of streak, making a primitive groove

Question 20

What do epiblast cells do after primitive groove formation?

Answer 20

• migrate towards streak, detach from epiblast, and slip beneath it into interior of embryo - called invagination
• invaginating epiblast cells invade hypoblast and displace its cells
• by day 16 most of the hypoblast cells are replaced - now called the endoderm

Question 21

What is the ectoderm?

Answer 21

The remaining epiblast cells

Question 22

What becomes the mesoderm?

Answer 22

• some invaginated epiblast cells stay in space between new ectoderm and endoderm
• once mesoderm and endoderm are formed, epiblast cells no longer migrate towards primitive streak

Question 23

What structures does the endoderm give rise to?

Answer 23

• GI tract
• liver, pancreas
• lung
• thyroid

Question 24

What structures does the ectoderm give rise to?

Answer 24

• CNS and neural crest
• skin epithelia
• tooth enamel

Question 25

What structures does the mesoderm give rise to?

Answer 25

• blood - endothelial cells, RBCs, WBCs
• muscle - smooth, skeletal, cardiac
• gonads, kidneys, adrenal cortex
• bone, cartilage

Question 26

What is the notochord formation?

Answer 26

• happens on day 13+
• rod-like tube structure formed of cartilage-like cells
• forms along embryo midline (from primitive streak), under the ectoderm, and grows towards the cranial end
• acts as a key organising centre for neurulation (CNS formation) and mesoderm development

Question 27

What is the neural plate?

Answer 27

• notochord controls neural plate for neurulation
• neural plate is area of thickened ectoderm that sits on top of embryo

Question 28

How does neurulation work? (Day 15)

Answer 28

• notochord signals direct the neural plate ectoderm to invaginate forming neural groove
• this creates two ridges (neural folds) running across cranio-caudal axis
• neural crest cells become specified in neural folds
• few days later, neural folds move together over neural groove and ultimately fuse to form a hollow tube
• neural tube is overlaid with epidermis (ectoderm)
• neural crest cells from folds migrate down

Question 29

What happens to the neural tube after it is initially formed?

Answer 29

• initially open at each end
• closure at head end at day 23
• closure at tail end at day 27
• closure at head precedes formation of brain structures

Question 30

What is anencephaly?

Answer 30

• failure of neural tube closure
• absence of most of skull and brain
• arises from failure to close at the head end (1/10,000 births)

Question 31

What is spina bifida?

Answer 31

• neural tube open at birth near tail end
• usually lower spine due to failure to close tail end - varying severity
• 0.4-5/1000 births

Question 32

What are neural crest cells?

Answer 32

• ectoderm derived, plastic and migrate extensively during development
• 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
• trunk NC –> dorsal root ganglia, sympathetic ganglia, adrenal medulla, aortic nerve clusters, melanocytes
• vagral and sacral NC –> parasympathetic ganglia and enteric NS ganglia

Question 33

What do defects in neural crest migration or specification lead to?

Answer 33

Diverse birth defects including:

• pigmentation disorders
• deafness
• cardiac defects
• facial defects
• failure to innervate gut

Question 34

What is somitogenesis?

Answer 34

• formation of somites - happens after neural tube formation
• somites arise from paired blocks of paraxial mesoderm flanking the neural tube and notochord on either side
• blocks of paraxial mesoderm condense and bud off in somite pairs
• somitogenesis commences at the head end and progresses down the long axis of the embryo
• rate of ‘budding’ or appearance of somite pairs is species-specific, as is the number of pairs
• humans 1 pair/90 min, 44 pairs

Question 35

What do somites initially divide into in terms of embryonic tissue?

Answer 35

• sclerotome - goes on to form vertebrae and rib cartilage
• dermomyotome - which in turn subdivides to form:
• dermatome - gives rise to dermis of skin, some fat and connective tissues of neck and trunk
• myotome - forms muscles of embryo

Question 36

Describe the formation of the gut tube (day 16+)?

Answer 36

The primitive gut arises from two 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
• this folding pinches off part of the yolk sac to form the primitive gut
• primitive gut then patterned into: foregut, midgut, hindgut

Question 37

What does the foregut include?

Answer 37

• oesophagus
• stomach
• upper duodenum
• liver
• gallbladder
• pancreas

Question 38

What does the midgut include?

Answer 38

• lower duodenum and remainder of small intestine
• ascending colon
• first 2/3 of transverse colon

Question 39

What does the hindgut include?

Answer 39

• last 1/3 of transverse colon
• descending colon
• rectum
• upper anal canal

Question 40

How does the heart develop?

Answer 40

• begins as a tube of mesoderm around day 19
• beating and pumping commences around day 22
• foetal heartbeat detectable from 6 weeks gestational age

Question 41

How do the lungs develop?

Answer 41

• arise from lung bud, an endodermal structure adjacent to the foregut, in the 4th week of development
• lung bud splits into two at the end of the 4th week and progressively branches through development

Question 42

How do gonads develop?

Answer 42

• forms from mesoderm as bipotential (i.e. not committed to testis or ovary) structures known as gonadal/genital ridges
• 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
• XX embryos - absence of SRY leads to gonadal cells adopting a granulosa cell fate and ovary development, requiring reinforcement by FOXL2, a TF essential for ovary development