TARGET DECK: MED::I::Morphology and Development::Embryology::01 - Human Embryology Introduction

Self Evaluation on Histology Lab

DateTimeGroups
18 May14:00–17:00G1, G2, G3
19 May14:00–17:00G3, G4, G6
GroupArrival TimeDate
G114:0018 May
G215:0018 May
G516:0018 May
G314:0019 May
G415:0019 May
G616:0019 May

Program

  • Human Reproduction
  • Transport of Gametes and Fertilization
  • Cleavage and Implantation
  • Formation of Germ Layers and Early Derivatives
  • Establishment of the Basic Embryonic Body Plan
  • Placenta and Fetal Membranes
  • Molecular Basis for Embryonic Development
  • Oogenesis, embryonic development and offspring from female iPSC-derived PGCLCs
  • Self-Organization of the in vitro attached human embryo
  • Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis

  • CarlsonHuman Embryology & Developmental Biology
  • SadlerLangman’s Medical Embryology
  • Moore & PersaudThe Developing Human: Clinically Oriented Embryology
  • Schoenwolf et al.Larsen’s Human Embryology

Embryology — Definition and Periods

Definition

Embryology is the branch of medicine that studies Human Development. Development begins at fertilization, approximately 14 days after the last normal menstrual period.

  • The embryonic period covers the first 8 weeks of development.
  • The fetal period begins in the 9th week.
  • Most visible advances occur during the 3rd to 8th week.

Human Pregnancy Periods

Clinical (Obstetric) Subdivision — Trimesters

Physicians use trimesters: three-month periods starting from the onset of the last menstrual period (LMP).

TrimesterApproximate Weeks from LMP
First0–13 weeks
Second14–26 weeks
Third27–40 weeks

Embryological Subdivision — Periods

Human embryologists use three periods:

PeriodTiming
Period of the eggFertilization → end of 3rd week
Period of the embryoBeginning of 4th week → end of 8th week
Period of the fetusBeginning of 3rd month → birth

Phases of Human Embryogenesis

Key Phases

Human embryologists identify the following sequential phases:

  1. Gametogenesis — formation of gametes (egg and sperm)
  2. Fertilization — joining of gametes to form the zygote
  3. Cleavage — rapid cell divisions forming first the morula (mulberry-like cluster), then the blastocyst (hollow ball of cells with a central cavity)
  4. Gastrulation — rearrangement of cells into three primary germ layers (ectoderm, mesoderm, endoderm) to form the embryonic disc
  5. Formation of the tube-within-a-tube body plan — body folding converts the embryonic disc into a C-shaped body:
    • Outer ectodermal tube (future skin)
    • Inner endodermal tube (gut tube)
    • Mesoderm interposed between the two tubes
  6. Organogenesis — formation of organ rudiments and organ systems

Timetable of Prenatal Development

Info

Key early stages by approximate day post-fertilization:

StageEvent
Stage 2 beginsEarly cleavage
Stage 3 beginsMorula
Stage 4Trophoblast differentiation
Stage 5 beginsImplantation begins
~Day 7–12Implantation
Bilaminar embryonic discProchordal plate visible

Developmental Biology Frontiers

Historical Milestones

  • 1995 — Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric F. Wieschaus awarded the Nobel Prize in Physiology or Medicine for discovery of genes controlling embryonic development. Critical role of genes, signaling molecules, receptors, and molecular factors in regulating early embryonic development is being delineated.
  • 1997 — Ian Wilmut and colleagues produced the first cloned mammal (Dolly the sheep) using somatic cell nuclear transfer (SCNT). Interest in human cloning has generated considerable debate due to social, ethical, and legal implications; concern exists about increased birth defects in cloned neonates.
  • 2021 — Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis demonstrated.

Getting Ready for Pregnancy — The Reproductive Organs

Info

The reproductive organs produce and transport germ cells (gametes) from the gonads (testes or ovaries) to the site of fertilization, which usually occurs in the ampulla of the uterine tubes.

  • Vagina — serves as excretory passage for menstrual fluid and forms the inferior part of the birth canal.
  • Uterus — pear-shaped organ composed of two parts:
    • Body — expanded superior two thirds
    • Cervix — cylindrical inferior third

Uterus — Wall Layers

The wall of the body of the uterus consists of three layers:

LayerDescription
PerimetriumThin external peritoneal layer
MyometriumThick smooth muscle layer
EndometriumInternal layer (three sublayers)

Endometrium Sublayers

SublayerDescription
Compact layerDensely packed connective tissue around terminal ducts of uterine glands
Spongy layerHighly vascularized connective tissue containing dilated uterine glands
Basal layerContains the blind ends of uterine glands

Gametogenesis

Definition

Gametogenesis is the formation of germ cells.

  • Spermatogenesis in males
  • Oogenesis in females

Sperms and oocytes are highly specialized gametes containing 23 chromosomes instead of 46, obtained through meiosis.


Normal Gametogenesis

Important

  • Sperm and oocytes each contain half the required chromosome number (23 instead of 46).
  • Chromosome number is reduced during meiosis — a special type of cell division occurring only during gametogenesis.
  • In males: spermatogenesis
  • In females: oogenesis

Spermatogenesis

Overview

  • Primordial germ cells (PGCs) derive from the epiblast (blastoderm) and remain dormant from the 6th week of embryonic development until puberty.
  • Primordial sperms (spermatogonia) remain dormant in the seminiferous tubules of the testes.
  • After puberty:
    1. Spermatogonia increase in number by mitosis
    2. They grow and transform into primary spermatocytes
    3. First meiotic division → two haploid secondary spermatocytes (half the size of primary)
    4. Second meiotic division → spermatids (half size)
    5. Spermatids differentiate into spermatozoa via spermiogenesis

Timeline and Storage

  • When spermiogenesis is complete, sperms enter the lumen of the seminiferous tubules.
  • They then move to the epididymis, where they are stored and become functionally mature.
  • Spermatogenesis requires approximately 2 months for completion.
  • Continues throughout the reproductive life of a male.

Primordial Germ Cells — Origin

Important

  • Primordial germ cells (PGCs) can be identified during the 4th–6th week of gestation within an extraembryonic membrane called the yolk sac.
  • Their lineage constitutes the germ line — a series of cells that form the gametes.
  • One of the first events in the developing embryo is that the germ line is set aside for the next generation.

Mature Sperm Cell — Structure

Sperm Anatomy

  • Acrosome — cap-like organelle on the anterior two thirds of the head; contains enzymes that facilitate sperm penetration during fertilization (penetration of the zona pellucida).
  • Tail — provides motility; consists of three parts:
PartLengthFunction
Middle piece~7 µmContains mitochondria; produces energy for lashing movements
Principal piece~40 µmMain locomotor segment
End piece5–10 µmTerminal segment
  • Hox genes influence microtubule dynamics at the molecular level, shaping the sperm head and forming the tail.

At Puberty — Hormonal Control of Spermatogenesis

  • Testosterone secretion stimulates:

    • Development of secondary sex characteristics
    • Growth of the testes
    • Maturation of seminiferous tubules
    • Commencement of spermatogenesis → 150 to 275 million spermatozoa per day in humans
  • Sertoli cells differentiate into a system of seminiferous tubules.

  • Dormant PGCs resume development, divide by mitosis, then differentiate into spermatogonia.

  • Spermatogonia are located immediately under the basement membrane surrounding the seminiferous tubules.

  • Adjacent Sertoli cells are interconnected by tight junctions → establish the blood-testis barrier (testis is an immune-privileged site).

  • Developing spermatogonia reside within an immune-privileged site during development.

https://unibo.smartzoom.com/s1241/course1776/f1815/i1823/


Major Functions of Sertoli Cells

Function
Maintenance of the blood-testis barrier
Secretion of tubular fluid (10–20 µL/g of testis/h)
Secretion of androgen-binding protein
Secretion of estrogen and inhibin
Secretion of various proteins (growth factors, transferrin, retinal-binding protein, metal-binding proteins)
Maintenance and coordination of spermatogenesis
Phagocytosis of residual bodies of sperm cells

What are the major functions of Sertoli cells?

  1. Maintain blood-testis barrier; 2. Secrete tubular fluid; 3. Secrete androgen-binding protein; 4. Secrete estrogen and inhibin; 5. Secrete growth factors and other proteins; 6. Maintain/coordinate spermatogenesis; 7. Phagocytose residual bodies of sperm cells.

Capacitation

Capacitation — Final Step of Sperm Maturation

Capacitation consists mainly of changes in the acrosome that prepare it to release the enzymes required to penetrate the zona pellucida (a shell of glycoprotein surrounding the oocyte).

  • Capacitation takes place within the female genital tract.
  • Requires contact with secretions of the oviduct.
  • Spermatozoa used in IVF are artificially capacitated (using media of calcium ions, bicarbonate, and serum albumin).
  • Spermatozoa with defective acrosomes may be injected directly into oocytes (ICSI) to assist reproduction.

Practice Question — Acrosome Mutation

Exam Question

What would be a direct consequence of a single point mutation that modifies the proteins inside the acrosome?

  • a. Inability to dissolve zona pellucida’s glycocalyx ✓
  • b. Impairment of sperm capacitation
  • c. None of them
  • d. Impairment of sperm motility
  • e. Failure to complete spermatogenesis

Oogenesis: From Oogonia to Oocytes

Timeline of Oogenesis

StageEvent
Fetal periodOogonia proliferate by mitosis and enlarge to form primary oocytes
BirthAll primary oocytes have completed prophase I of the first meiotic division; arrested here until puberty
Just before ovulationPrimary oocyte completes first meiotic division with unequal cytoplasm division → 1 polar body (degenerates) + secondary oocyte (receives most cytoplasm)
OvulationNucleus of secondary oocyte begins second meiotic division
FertilizationSecond meiotic division completed → second polar body formed

Important

  • The secondary oocyte is large and visible to the naked eye.
  • Up to 2,000,000 primary oocytes are present in the ovaries of a neonate.
  • Most regress during childhood; by puberty, no more than 40,000 remain.
  • Of these, only ~400 oocytes mature into secondary oocytes and reach ovulation.

Comparison Between Male and Female Gametes

FeatureSpermatozoaOocytes
SizeSmallMassive
MotilityMotileImmotile
CytoplasmScantAbundant
Chromosome complement23, X or 23, Y23, X only
TypesTwo types (X or Y-bearing)One type

Info

The difference in sex chromosome complement forms the basis of primary sex determination.


Gametogenesis Differences: Males vs. Females

After PGCs Enter the Genital Ridge

After PGCs enter the genital ridge, they stop migrating, undergo 2–3 mitoses, and enter the premeiotic stage.

FeatureMaleFemale
PGC arrest6th week of embryonal developmentEnter meiotic prophase as primary oocytes at 5th month of fetal development
Meiosis beginsAt pubertyFetal life (5th month)
Meiosis inhibitorYes — male meiosis inhibitor produced by Sertoli cellsNo

Key Concept — Cell Autonomy of Oogenesis

  • If male PGCs (XY) are transplanted into female (XX) embryos, they follow the female PGC course, regardless of their chromosome constitution.
  • PGCs that fail to reach the gonads also progress through meiosis as oocytes, regardless of genotype.
  • All PGCs are programmed to be oocytes — this is cell autonomous and Tet1-dependent (a transcription factor that erases epigenetic marks in DNA).
  • In the male genital ridge, a male meiosis inhibitor (produced by Sertoli cells) overrides this default.

Male vs. Female — Full Comparison

FeatureMaleFemale
PGC dormancyFrom 6th embryonic week until pubertyUndergo a few more mitoses → oogonia
Meiosis onsetAt puberty5th month of fetal development (all oogonia begin meiosis → primary oocytes)
State of arrestNot arrested after pubertyMeiotic arrest in prophase I until puberty; second arrest at metaphase II until fertilization
ProductionContinuous, puberty to deathCyclic; ~1 oocyte per month from puberty to menopause (~50 years)
Meiosis completionCompleted during spermatogenesisCompleted only if fertilization occurs

Sacrococcygeal and Oropharyngeal Teratomas

Info

Teratomas can arise from primordial germ cells that fail to complete normal migration to the gonads. Examples include:

  • Sacrococcygeal teratoma (fetal)
  • Massive oropharyngeal teratoma

Female Reproductive Cycles

Ovarian Cycle

Info

The ovarian cycle is the process that leads to the development of a mature follicle, followed by rupture and oocyte expulsion, ready for fertilization.


Ovarian Follicles — Development Stages

Four Stages of Follicular Development from Primordial Follicles

StageKey Features
1. Primordial folliclePrimary oocyte surrounded by flat follicular cells
2. Unilaminar primary follicleFollicular cells become cuboidal; oocyte grows to ~100–150 µm
3. Multilaminar primary follicleFollicular cells proliferate and stratify → granulosa cells; zona pellucida appears; theca folliculi develops
4. Secondary (antral) follicleLiquor folliculi accumulates among granulosa cells; antrum forms
5. Graafian (mature) follicleFully mature; ready for ovulation

FSH Dependence

  • Development of primordial and primary follicles is independent of FSH — triggered by uncharacterized local ovarian factors.
  • Secondary and later follicles are under the influence of FSH.

https://unibo.smartzoom.com/s1241/course1776/f1815/i2437/


Ovarian Follicles — Primary Follicles

Unilaminar Primary Follicle

  • Primary oocyte grows to ~100–150 µm with enlarged nucleus.
  • Follicular cells become cuboidal in shape.

Multilaminar Primary Follicle

  • Follicular cells proliferate and stratify → now called granulosa cells.
  • An amorphous substance — the zona pellucida — appears, separating the oocyte from surrounding follicular cells.
  • Stromal or granulosa cells form:
    • Theca interna — richly vascularized cellular layer
    • Theca externa — mostly fibrous connective tissue

Estradiol Synthesis

Theca interna cells produce androstenedione (male sex hormone) → enters granulosa cells → converted by aromatase to estradiol (estrogen).


Ovarian Follicles — Secondary Follicles & Graafian Follicle

Secondary Follicle

  • Similar to primary follicle but with accumulations of liquor folliculi among granulosa cells.
  • Continued granulosa cell proliferation depends on FSH from basophil cells of the anterior pituitary.

Graafian (Mature) Follicle

  • Fully mature, bulging on the surface of the ovary.
  • LH surge allows discharge of the mature oocyte.
  • After ovulation, the follicle undergoes atresia; granulosa cells → granulosa lutein cells; theca cells → theca lutein cells.
  • Together they form the corpus luteum, which produces progesterone.

Follicular Development — Summary of Key Features

Development of an ovarian follicle is characterized by:

  1. Growth and differentiation of a primary oocyte
  2. Proliferation of follicular cells
  3. Formation of the zona pellucida
  4. Development of a connective tissue capsule — theca folliculi

Info

Thecal cells produce an angiogenic factor that promotes growth of blood vessels providing nutritive support for follicular development.


Ovulation

Process of Ovulation

  1. Follicular cells divide actively → antrum forms (containing follicular fluid) → follicle is now called a secondary follicle.
  2. Primary oocyte is surrounded by corona radiata projecting into the enlarged antrum.
  3. Follicle continues to enlarge → forms a bulge on the ovarian surface.
  4. A small oval avascular spot — the stigma — appears on the bulge.
  5. Before ovulation: secondary oocyte and some cells of the cumulus oophorus detach from the interior.
  6. Expelled secondary oocyte is surrounded by:
    • Zona pellucida (acellular glycoprotein coat)
    • Corona radiata (radially arranged follicular cells)
    • Cumulus oophorus cells

https://unibo.smartzoom.com/s1241/course1776/f1815/i1827/


Ovulation — Hormonal Timeline

Time (hours from LH surge)Event
0Ovulatory surge of LH and FSH
~15Germinal vesicle breaks down
~20Chromosomes in metaphase I; first meiotic division completed → secondary oocyte + first polar body
~37Second meiotic metaphase arrest; ovulation occurs

Important

  • Ovulation follows within 24–36 hours of the LH surge.
  • High estrogen level in blood elicits the LH surge (positive feedback from granulosa cells).
  • LH surge causes the stigma to rupture, expelling the secondary oocyte with follicular fluid.
  • Plasmins and matrix metalloproteinases (MMPs) also contribute to stigma rupture.

Corpus Luteum

Important

Under the influence of LH, the walls of the ruptured follicle develop into an endocrine glandular structure — the corpus luteum — which secretes primarily progesterone and some estrogen.

ScenarioOutcome
Oocyte fertilizedCorpus luteum enlarges → corpus luteum of pregnancy; degeneration prevented by hCG (human chorionic gonadotropin)
Oocyte not fertilizedCorpus luteum degenerates 10–12 days after ovulation → corpus luteum of menstruation
After degenerationTransformed into corpus albicans (white scar tissue)

Why Is Folliculogenesis Selectively Stimulated in Only a Few Follicles Each Month?

Info

  • Uncertain mechanism.
  • Possibility 1: Follicles become progressively more sensitive to stimulating effects of FSH as they advance in development.
  • Possibility 2: Selection is regulated by a complex feedback system between pituitary and ovarian hormones and growth factors.

Hormonal Profile — Menstrual Cycle

Info

The menstrual cycle is the period during which the oocyte matures, is ovulated, and enters the uterine tube. Estrogen and progesterone (produced by ovarian follicles and corpus luteum) cause cyclic changes in the uterine endometrium.


Viability of Oocytes and Sperms

GameteViability
OocyteUsually fertilized within 12 hours of ovulation; cannot be fertilized after 24 hours; degenerates shortly after
SpermatozoaMost do not survive more than 24 hours in the female genital tract

Info

  • Some sperms are captured in folds of the cervical mucosa, gradually released into the cervical canal and through the uterus into the uterine tubes.
  • Semen and oocytes can be frozen and stored for many years for use in assisted reproduction.


Summary

  • Gametogenesis — formation of gametes via meiosis
  • Ovarian Cycle — folliculogenesis, ovulation, corpus luteum formation/degeneration

https://studentconsult.inkling.com/read/larsen-human-embryology-schoenwolf-5/videos/animation-1-1


Practice Questions

Question 1

Spermatogonia, derived from primordial germ cells, divide by mitosis during which period(s)?
✓ Continuously throughout postpuberty life

Question 2

Most oocytes become atretic and degenerate during which period(s)?
✓ Between the fifth and seventh fetal months

Question 3

In oocytes, the first meiotic division is completed during which period(s)?
✓ In response to the peak of FSH and LH during the menstrual cycle

Question 4

During the average menstrual cycle, LH and FSH levels are highest during which period?
✓ Immediately prior to ovulation

Question 5

Following ovulation, the corpus luteum is formed from which structure?
✓ The theca externa, theca interna, and granulosa

Question 9

The “definitive oocyte” (Haploid, 1N) is generated as a result of which of the following?
✓ In response to fertilization following ovulation

Question 10

Binding of sperm to integrin α6β1 mediates which of the following?
✓ Fusion of sperm and oocyte plasma membranes


[!tldr] TLDR — Full Summary

  • Embryology studies human development from fertilization (~14 days after LMP) through birth; the embryonic period is weeks 1–8, the fetal period begins week 9.
  • Pregnancy is divided into three obstetric trimesters or three embryological periods (egg, embryo, fetus).
  • Phases of embryogenesis: gametogenesis → fertilization → cleavage (morula → blastocyst) → gastrulation (ectoderm, mesoderm, endoderm) → tube-within-a-tube body plan → organogenesis.
  • Uterus has three wall layers (perimetrium, myometrium, endometrium); endometrium has compact, spongy, and basal sublayers.
  • Gametogenesis reduces chromosome number from 46 to 23 via meiosis.
  • PGCs originate in the yolk sac (weeks 4–6), migrate to the genital ridge; all PGCs are intrinsically programmed to become oocytes (Tet1-dependent cell-autonomous process); in males, Sertoli cell–derived meiosis inhibitor overrides this.
  • Spermatogenesis: PGCs dormant from week 6 until puberty; at puberty testosterone drives spermatogonia → primary spermatocytes (meiosis I) → secondary spermatocytes → spermatids → spermatozoa (spermiogenesis); ~2 months; 150–275 million/day; stored in epididymis; continuous from puberty to death.
  • Sperm structure: head (nucleus + acrosome with lytic enzymes) + tail (middle piece with mitochondria, principal piece, end piece).
  • Capacitation: final maturation step occurring in the female genital tract (oviduct secretions); acrosome primed to release enzymes for zona pellucida penetration; artificially induced in IVF with Ca²⁺, bicarbonate, serum albumin.
  • Oogenesis: oogonia → primary oocytes (5th fetal month, arrested at prophase I) → at puberty/LH surge, complete meiosis I → secondary oocyte + 1st polar body → arrested at metaphase II → fertilization completes meiosis II → second polar body; ~2,000,000 at birth → ~40,000 at puberty → ~400 ovulated over a lifetime.
  • Follicular development (4 stages): primordial → unilaminar primary → multilaminar primary (zona pellucida, theca, granulosa cells, aromatase-driven estradiol synthesis) → secondary/antral (FSH-dependent) → Graafian.
  • Ovulation: LH surge (triggered by high estrogen) → stigma rupture (plasmins, MMPs) → expulsion of secondary oocyte arrested in metaphase II; oocyte surrounded by zona pellucida, corona radiata, cumulus oophorus.
  • Corpus luteum: formed from granulosa lutein + theca lutein cells post-ovulation; secretes progesterone (+estrogen); maintained by hCG if fertilization occurs (corpus luteum of pregnancy); degenerates at 10–12 days if not (corpus luteum of menstruation) → corpus albicans.
  • Gamete viability: oocyte fertilizable for ~12 h (max 24 h); most spermatozoa survive <24 h in female tract.