Overview
This lecture introduces the module on human development by laying out the terminology and timeline of gestation, then tracing early development from fertilisation through implantation and gastrulation to the formation of the three primary germ layers and their derivatives. It closes with teratogenesis: what a teratogen is, why the timing of exposure determines the defect produced, and thalidomide as a worked example linking clinical observation to developmental biology.
Why study development, and terminology
The module (four lectures: overview/teratogenesis, heart development, GI and respiratory development, urogenital development) is motivated by three clinical uses of developmental knowledge: understanding risk factors in pregnancy (to advise patients), understanding assisted reproductive technology (ART, to counsel would-be parents), and understanding the basis of birth defects (to help parents understand a child’s disorder and to judge when prenatal screening is indicated).
Stage terminology by gestational time:
- Conceptus: fertilisation to 2 weeks (zygote, then blastocyst)
- Embryo: weeks 3-8
- Fetus: weeks 9-38/40
- Birth occurs at approximately 38-40 weeks.
A teratogen is any compound or event that impinges on the developing individual, disrupts development, and leads to malformation or impaired function later in life.
Broad trimester milestones (illustrative, not exhaustive):
- First trimester: conception to 4 weeks (zygote/blastocyst; early spinal cord, nervous, GI, heart and lung development begins); 8 weeks (rudimentary face, detectable fetal heartbeat, now called an embryo); 12 weeks (moves limbs and digits, fingerprints present, sex distinguishable, now called a fetus).
- Second trimester: 16 weeks (lanugo, coordinated movements); 20 weeks (audible heartbeat, thumb-sucking); 24 weeks (vernix caseosa, eyes open).
- Third trimester: 28 weeks (rudimentary breathing movements); 32 weeks (sleep-wake cycles, responds to sound); 36-38 weeks (lanugo mostly gone, gaining maternal immunities).
Fertilisation to implantation (days 1-9)
Sequence of early cleavage and pre-implantation development:
- Fertilisation occurs in the oviduct.
- Day 1: first cleavage, 2-cell stage.
- Day 2: 4-cell stage.
- Day 3: early morula.
- Day 4/5: advanced morula.
- The dividing cells are blastomeres; the whole structure is enclosed by the zona pellucida throughout this period.
- Day 5/6: blastocyst stage; the zona pellucida is shed (“hatching”).
- Day 7: implantation — the blastocyst attaches to the uterine wall.
Clinical correlate: IVF favours transferring blastocysts at the Day 5 stage because they have already hatched, are competent to implant, and are easier to quality control than earlier-stage embryos.
Blastocyst structure (Day 5, viewed from inside): a trophoblast outer layer, an inner cell mass (ICM) which becomes the embryo, and a fluid-filled cavity, the blastocoel.
Continuing after implantation:
- Day 8: the trophoblast becomes multi-layered — cytotrophoblast (closest to the ICM) and syncytiotrophoblast (the outer layer, which invades the endometrium).
- Day 9: the amniotic cavity forms as the ICM separates from the trophoblast.
Extraembryonic membranes and the bilaminar disc (days 9-10)
By Day 9 the ICM has become a two-layered blastodisc: the epiblast and hypoblast, which together form the embryo proper. Alongside this, extraembryonic structures develop: the blastocoel, the amniotic cavity, and the amnion (which bounds it).
By Day 10, trophoblast invasion of the endometrium is complete and the yolk sac forms beneath the hypoblast. Structures at this stage are classified as:
- Embryonic: epiblast, hypoblast
- Extraembryonic: amnion, amniotic cavity, yolk sac
Gastrulation and formation of the three germ layers
Gastrulation is the process by which the three primary germ layers are formed, beginning around day 12.
Sequence of events:
- ~Day 12: cells of the epiblast migrate toward the primitive streak, entering first at the node (the anterior end of the streak). At the primitive streak, migrating cells dive underneath the epiblast (ingression/involution).
- ~Days 14-15 (early involution): the earliest involuting cells laterally displace the hypoblast cells, and this displaced/replacing layer becomes the endoderm (forms ventrally).
- ~Days 15-16 (late involution): cells ingressing later no longer displace the hypoblast; instead they insert as a new layer between the ectoderm (the remaining epiblast surface layer) and the endoderm — this new middle layer is the mesoderm.
Clinical correlate: a genetic abnormality or teratogen exposure that prevents proper epiblast cell migration causes major impairment of gastrulation, leading to miscarriage.
Development and subdivision of the mesoderm
As gastrulation proceeds (~days 19-22), the ectoderm itself differentiates into neural ectoderm (midline, forms the neural plate, then neural groove, then neural folds) and non-neural ectoderm (flanking regions). Beneath the neural ectoderm at the midline, the notochord forms, with paired somites (paraxial mesoderm) lying either side of it.
Mesoderm progressively subdivides, moving from the midline (notochord) outward:
- Notochord (axial)
- Somites (paraxial mesoderm) — segmented, paired, flank the notochord
- Intermediate mesoderm — lateral to the somites
- Lateral plate mesoderm — the outermost mesoderm, furthest from the notochord; this later splits into two layers:
- Somatic (parietal) lateral plate mesoderm
- Splanchnic (visceral) lateral plate mesoderm
By ~22 days gastrulation is complete, with the neural tube, notochord, paired somites, intermediate mesoderm, and somatic/splanchnic lateral plate mesoderm all visible in cross-section, sitting above the endoderm.
Full primary germ layer derivative map
This is the completed version of the branching diagram (Epiblast → Ectoderm / Mesoderm / Endoderm):
- Ectoderm
- Neural: brain, spinal cord, neural crest
- Non-neural: epidermis, hair, nails, skin glands
- Mesoderm
- Notochord: intervertebral discs
- Somites: vertebrae and ribs, skeletal muscle, dorsal dermis
- Intermediate mesoderm: urogenital system
- Lateral plate:
- Splanchnic: heart, circulatory system, visceral serosa (coverings of organs)
- Somatic: body wall serosa, ventral dermis, limb connective tissue
- Endoderm: digestive tract (including pancreas, liver, gallbladder), respiratory tract, associated glands
Teratogenesis
Teratogenesis is the process by which congenital malformations are produced in an embryo or fetus. If a compound or event interferes with development in a tissue/organ system, and that system acquires a defect as a result, the compound/event is a teratogen and the offspring has a congenital anomaly.
The period of highest susceptibility to a given teratogen is the time when the affected tissue or organ system is undergoing its major developmental events. Overall risk of congenital anomaly rises steeply from near zero at fertilisation, peaks sharply around week 5 (embryonic period), and then declines gradually across the fetal period (weeks 8-38) toward parturition (~week 38). The conceptus period (weeks 1-2) is usually not susceptible to teratogens.
Structure-specific windows of peak sensitivity during the embryonic period (weeks 3-8):
- CNS: roughly weeks 3-6 (brain remains sensitive much later too, up to weeks 20-36, into the fetal period)
- Heart: weeks 3-6 (week 5 marked as high likelihood of producing heart defects)
- Eye: weeks 4-8
- Ear: weeks 4-8ish
- Leg and arm: weeks 4-6ish
- Palate/teeth: weeks 6-8 (weeks 6-7 marked as high likelihood of producing craniofacial defects)
- External genitalia: weeks 7-8
Fetal-period sensitivity is generally reduced compared with the embryonic period, though the brain remains an exception.
Thalidomide: a worked example
Thalidomide was taken by pregnant women for morning sickness during roughly weeks 4-8 of gestation, which coincides with the sensitivity window for limb (and other) development.
Mechanism: clinical developmental biology studies showed thalidomide stops the cell division necessary for limb outgrowth.
Timing determined the defect:
- Exposure at 5 weeks: limb development arrested early → no or very small limbs.
- Exposure at 6 weeks: limb development arrested later → some limb elements present, with forelimbs more developed than hindlimbs.
- Exposure at 8 weeks: limb development mostly finished by the time of exposure → no defects.
This illustrates the general teratogenesis principle: the developmental stage reached at the moment of exposure, not just the agent itself, determines the resulting malformation.
Self-test
- Define a teratogen.
- List the three stage names (conceptus, embryo, fetus) with their gestational time windows.
- Describe the sequence of events from fertilisation to implantation, day by day, including the fate of the zona pellucida.
- Why is a Day 5 blastocyst preferred for IVF transfer?
- Distinguish the trophoblast from the inner cell mass (ICM), and cytotrophoblast from syncytiotrophoblast.
- Describe the steps of gastrulation, from epiblast cell migration to the formation of endoderm and then mesoderm, including the role of the primitive streak and node.
- What is the clinical consequence of major impairment of gastrulation?
- List, in order from the midline outward, the subdivisions of the mesoderm, and give one adult derivative of each.
- Distinguish somatic (parietal) from splanchnic (visceral) lateral plate mesoderm by their derivatives.
- Explain why the period of highest susceptibility to a teratogen differs between organ systems.
- A pregnant patient took a teratogenic drug at 5 weeks’ gestation and her baby was born with very small, underdeveloped limbs. A second patient took the same drug at 8 weeks and her baby’s limbs were normal. Explain this difference in outcome.
- Integrative: explain how the timing of gastrulation events (early vs late epiblast cell involution) determines which germ layer is formed, and how this same timing principle (developmental stage at exposure) reappears in the thalidomide example.
Answers
Reveal answers
- A teratogen is any compound or event that impinges on the developing individual, disrupts development, and leads to malformation or impaired function later in life.
- Conceptus: fertilisation to 2 weeks. Embryo: weeks 3-8. Fetus: weeks 9-38/40.
- Fertilisation occurs in the oviduct. Day 1: first cleavage (2-cell stage). Day 2: 4-cell stage. Day 3: early morula. Day 4/5: advanced morula. Throughout this the embryo is enclosed by the zona pellucida. Day 5/6: blastocyst stage, and the zona pellucida is shed (“hatching”). Day 7: implantation, the blastocyst attaches to the uterine wall.
- A Day 5 blastocyst has already hatched, is competent to implant, and is easier to quality control than earlier-stage embryos, giving an increased live birth rate when used in IVF.
- The trophoblast is the outer layer of the blastocyst that will form placental/extraembryonic tissue; the ICM is the inner cluster of cells that becomes the embryo. Within the trophoblast, the cytotrophoblast is the inner layer closest to the ICM, while the syncytiotrophoblast is the outer layer that invades the endometrium.
- Cells of the epiblast migrate toward the primitive streak, entering first at the node, then dive underneath the epiblast (involution). Cells that involute early (~days 14-15) laterally displace the hypoblast cells, and this layer becomes the endoderm. Cells that involute later (~days 15-16) no longer displace the hypoblast but instead insert as a new layer between the ectoderm and endoderm, forming the mesoderm.
- Major impairment of gastrulation (e.g. from a genetic abnormality or teratogen preventing proper epiblast migration) leads to miscarriage.
- From midline outward: notochord (intervertebral discs); somites/paraxial mesoderm (vertebrae and ribs, skeletal muscle, dorsal dermis); intermediate mesoderm (urogenital system); lateral plate mesoderm (splits into splanchnic: heart, circulatory system, visceral serosa; and somatic: body wall serosa, ventral dermis, limb connective tissue).
- Splanchnic (visceral) lateral plate mesoderm gives rise to the heart, circulatory system and visceral serosa (organ coverings); somatic (parietal) lateral plate mesoderm gives rise to body wall serosa, ventral dermis and limb connective tissue.
- Each organ system has its own window of major developmental activity; the period of highest susceptibility to a teratogen for that system is whenever it is undergoing those significant developmental events, so different systems peak in sensitivity at different gestational weeks (e.g. heart ~week 5, palate/craniofacial ~weeks 6-7).
- At 5 weeks, limb development is early and highly active, so thalidomide’s arrest of cell division prevents limb outgrowth almost entirely, producing very small/no limbs. By 8 weeks, limb development is mostly finished, so the same exposure occurs after the sensitive window has passed and produces no defect.
- In gastrulation, the developmental “stage” of the involuting cell population (early vs late) determines its fate: early cells become endoderm, later cells become mesoderm, purely because of timing relative to the ongoing process. Thalidomide follows the same logic at the tissue level: the degree of limb malformation depends entirely on how far limb development had progressed at the moment of exposure (5 weeks: arrested early, no/small limbs; 6 weeks: arrested later, partial limbs; 8 weeks: development essentially complete, no defect). In both cases, outcome is set by timing relative to a developmental window, not by the agent/process alone.