Early Embryology

Week 1

DRUGS Stuff

Fertilisation

  • 300 million sperm are ejaculated during coitus, where only 200 successfully reach the oviduct for fertilisation - leaving 99.9% of sperm to die along the course of the female reproductive tract
  • Capacitation involves the modification of sperm (triggered by HCO3- in the vagina). Via the: soluble AC → cAMP cascade, the lipid & glycoprotein membrane composition is altered → membrane hyperpolarisation → increased sperm motility
  • Chemoattractant molecules are released by the follicle cells surrounding the ovulated egg to permit chemotaxis of the sperm
  • Sperm that reach the site of the egg migrate through the layer of follicle cells, and bind to the zona pellucida, fusing with the egg plasma membrane for successful fertilisation
Zona Pellucida

Humans have four major zona pellucida glycoproteins: ZP1, ZP2, ZP3 & ZP4, which are primarily produced by the growing oocyte.

  • ZP2 & ZP3 form the core filaments of the zona matrix.
  • ZP1 cross-links these filaments.
  • ZP4 contributes to structure and sperm interaction.
Sperm binding depends on mutiple zona proteins, an area of current research.

The Acrosome Reaction

  • The acrosome reaction involves hydrolytic enzymes that allow passage of the sperm through the zona pellucida
  • Exposed proteins in the sperm plasma membrane bind & fuse with the egg membrane
  • >1 sperm can bind the egg, however only 1 will fuse. There are two mechanisms that allow this:
    1. Fusion of first sperm → rapid depolarisation of the egg PM → temporary primary block to polyspermy → PM returns to resting membrane potential
    2. The egg cortical reaction.

The Egg Cortical Reaction

  • Fusion of sperm & egg → local increase in cytosolic calcium triggered by a paternal protein → cortical granules release enzymes which harden the zona pellucida
  • Sperm can no longer bind, preventing polyspermy
CLINICAL

Polyspermy

  • Occurs when >1 sperm fertilises a single oocyte
    • Normally, one maternal pronucleus and one paternal pronucleus form and then fuse to produce a diploid zygote
    • With polyspermy, one maternal pronucleus is present alongside two (or more) paternal pronuclei, resulting in an abnormal chromosome complement (e.g. triploidy if two sperm enter)
    • Each sperm contributes a centriole, which gives rise to a centrosome, resulting in extra centrosomes
  • Extra centrosomes produce extra spindle poles
    • Normally, two centrosomes organise microtubules into a bipolar mitotic spindle.
    • With polyspermy, there may be three or more centrosomes, giving rise to tripolar, tetrapolar, or multipolar spindles
    • As a result, chromosomes are pulled towards multiple spindle poles simultaneously
  • Chromosomes segregate incorrectly, producing aneuploid daughter cells
    • During anaphase, sister chromatids should separate equally to opposite spindle poles
    • Following cytokinesis, daughter cells may contain extra or missing chromosomes (aneuploidy).
    • Severe aneuploidy activates cell-cycle checkpoints and apoptosis, causing early embryonic death.
CLINICAL

Ectopic Pregnancy

  • The ampulla of the fallopian tube is the most common site for an ectopic pregnancy (~95%)
  • May be suspected with a lower than expected rise in hCG for gestation dates
  • In a patient with a suspected ectopic pregnancy perform a prgancy text, then confirm with transvaginal ultrasound
    • First line treatment: Salpingectomy
    • Second-line treatment: Salpingotomy if risk factors for infertility


EXPERIMENTAL

Literature Review for Fertilisation

    • Using sea urchins to research fertilisation
      • External fertilisation makes the process easier to observe and manipulate.
      • Large numbers of gametes can be collected for experiments.
    • Zona-free hamster eggs can be used to assess the fertilising capacity of human sperm in vitro.
      • The zona pellucida normally acts as the barrier to fertilisation - thus allowing human sperm to fertilise hamster eggs.
      • Hybrid zygotes fail to form

Recap

Egg + Sperm → 1 cell zygote → divides into two blastomeres: Blastomere A + Blastomere B = 1 embryo

Blastomere

  • A blastomere is each individual cell within the early embryo.
  • Similarly, the embryo is the entire collection of blastomeres.
  • Developmental stages:
    • Zygote (1 cell) = a single fertilised egg.
    • 2-cell stage = 2 blastomeres.
    • 4-cell stage = 4 blastomeres.
    • 8-cell stage = 8 blastomeres: cells up to this point are totipotent
  • By day 3, an embryo typically contains 7–9 totipotent blastomeres. Separation of one or more blastomeres at this stage can result in dichorionic diamniotic (DCDA) identical twins.
Compaction
  • This occurs around the 8-cell stage
EXPERIMENTAL • PMCID: PMC11151110 • PMID: 38841597

Retrospective Tracking of Somatic Mutations

  • Only one of the two blastomeres at the 2-cell stage contributes to the majority of cells in the future body.
  • The first 2-cell blastomere to divide to the 4-cell stage:
    • has a greater likelihood of undergoing asymmetric cell divisions
    • contributes more cells to the epiblast
    • forms the majority of the adult body
    • Challenges the assumption that all cells in the early embryo contribute equally to the adult body.

CLINICAL • PMCID: PMC5125156 • PMID: 27696105

Pre-Implantation Genetic Diagnosis (PGD)

  • DNA may be sampled from embryonic cells for genetic analysis.
  • Testing is offered to couples with known familial genetic mutations to select unaffected embryos before transfer during IVF.
CLINICAL

Dichorionic Diamniotic (DCDA) Twins

  • DCDA twins are formed by splitting at the blastomere stage (days 1–3).
  • Each blastomere is totipotent, allowing it to form an independent group of cells and a complete embryo, including the fetus, placenta, and extraembryonic membranes.
  • DCDA twins have two placentas and two amniotic sacs.
    • MCDA twins have one placenta and two amniotic sacs, formed by splitting at the morula or early blastocyst stage (days 4–8).
    • MCMA twins have one placenta and one amniotic sac, formed by splitting after the amnion forms (days 8–13).
  • When the two placentas implant in close proximity, they may fuse and appear as a single placenta.
    • Two placentas can be distinguished by the lambda sign (or twin peak sign) on first-trimester ultrasound. This appears as a triangular wedge of placental tissue projecting between the two gestational sacs, indicating a dichorionic pregnancy.

Morula

  • The morula is a solid ball of cells, with around 16-32 blastomeres
  • It is still surrounded by the zona pellucida
  • No cavity has yet formed

Blastocyst

  • This is formed after three divisions, with a total of 16 cells
  • The cells within the morula reorganise to form a cavity, the blastocoel - now recognised as a blastocyst
  • The blastocyst has an inner (embryoblast) and outer (trophoblast) cell mass
Feature Morula Blastocyst
Approx. day Day 3–4 Day 5–6
Number of cells About 16–32 cells More cells, with clear differentiation
Shape / appearance Solid ball of cells Hollow, fluid-filled structure
Cavity present? No cavity Yes — blastocoel
Main cell groups No clear inner/outer distinction yet Inner cell mass + trophoblast
Zona pellucida Still present Still present at first, then lost during hatching
Key event Compaction Hatching and implantation
Future fate Transitions into blastocyst Inner cell mass becomes embryo; trophoblast becomes placenta

Week 2

DRUGS Stuff

The Bilaminar Disc

  • This is formed after three divisions, with a total of 16 cells

Implantation

  • This is formed after three divisions, with a total of 16 cells
  • While fertilisation usually occurs within the fallopian tubes, it is not until some 6 days later that the cell mass implants into the uterine wall

Week 3

DRUGS Stuff

Morula

  • This is formed after three divisions, with a total of 16 cells

Written by: Natasha Wheeler
Edited by: ...

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK26843/
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC11151110/
    https://www.nice.org.uk/
  • British National Formulary (BNF). https://bnf.nice.org.uk/