Gastrulation, Neurulation & Ectoderm Derivatives
Timeline of Human Development
Human development traditionally divided into two macro-periods:
Embryonic period: 3^{rd}\text{ to }8^{th}\text{ week} (organogenesis-focused)
Fetal period: 9^{th}\text{ week to birth (≈38 weeks)} (growth & functional maturation)
Trimester breakdown (clinical gestational age counted from fertilization):
First trimester: 0–12\text{ weeks}
Second trimester: 13–25\text{ weeks}
Third trimester: 26–38\text{ weeks}
Key chronological landmarks (all values in weeks post-fertilization): 4, 8, 12, 16, 20, 24, 28, 32, 36, 38
Gastrulation & Germ Layer Formation
Lewis Wolpert: “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.”
Definition: coordinated, large-scale cell movements converting a single-layered blastoderm into a multi-layered embryo.
Outcomes & significance:
Establishes the three definitive germ layers:
Ectoderm (outer)
Mesoderm (middle)
Endoderm (inner)
Brings non-adjacent cell populations into proximity → permits inductive interactions that underlie organ formation.
Key morphological structures during gastrulation (human, 15–17\text{ days}):
Primitive streak (caudal-dorsal midline)
Primitive node (Hensen’s node/organizer) at streak’s cranial end
Oropharyngeal membrane (future mouth, cranial)
Cloacal membrane (future anus, caudal)
Cell fate map:
1st ingressing epiblast cells → replace hypoblast → definitive endoderm
Subsequent ingressing cells between epiblast & endoderm → intra-embryonic mesoderm
Non-ingressing epiblast → ectoderm
Node-derived midline cells → prechordal plate, head mesoderm, notochord (axial mesoderm)
Membrane breakdown events:
Oropharyngeal membrane ruptures → stomodeum (mouth)
Cloacal membrane ruptures → anal opening
Embryonic Germ Layers & Representative Derivatives
Ectoderm (superficial):
Epidermis, hair, nails, sebaceous & sweat glands
Central nervous system (brain, spinal cord)
Peripheral nervous system via neural crest & placodes
Pigment cells (melanocytes)
Craniofacial skeleton & odontoblasts (neural crest)
Adrenal medulla (chromaffin cells)
Special sense epithelia/lens/inner ear (placodes)
Mesoderm:
Notochord, paraxial mesoderm (somites → bone, skeletal muscle, dermis)
Intermediate mesoderm (urogenital system)
Lateral plate mesoderm (heart, blood vessels, limb skeleton, serous membranes)
Head mesoderm (cranial musculature, connective tissue)
Endoderm:
Epithelia of gastrointestinal & respiratory tracts, associated glands (liver, pancreas), pharyngeal epithelium, thyroid, parathyroid
Ectoderm: Neural Induction & CNS Development
Neural Induction
Defined as the process converting a patch of ectoderm into the neural plate (future CNS).
Requires interaction with underlying chordamesoderm/notochord (dorsal mesoderm).
Molecular Basis
Default ectodermal fate = epidermis under influence of BMP4.
BMP4 inhibition is necessary/sufficient for neural fate:
Antagonists Noggin, Chordin, Follistatin secreted by dorsal mesoderm bind BMP4 → prevent receptor activation.
Experimentally, loss of BMP signaling → ectoderm becomes neural tissue.
Resulting “default” neural tissue is anterior/forebrain-like.
Regionalization of Neural Plate
Posteriorizing signals (from mesoderm): FGF, WNT, Retinoic Acid (RA).
Sequential logic (Wolpert model):
\begin{aligned}
&\text{Ectoderm} &\xrightarrow{\text{BMP4}}& \text{Epidermis}\
&\text{Ectoderm} &\xrightarrow{\text{–BMP4}}& \text{Anterior neural plate}\
&\text{Anterior neural plate} &\xrightarrow{\text{+FGF/WNT/RA}}& \text{Posterior neural plate (hindbrain/spinal cord)}
\end{aligned}
Neurulation (Formation of Neural Tube)
Temporal window: \approx17–28\text{ days post-fertilization}.
Sequence of morphogenetic steps:
Shaping – elongation & narrowing of neural plate.
Elevation – formation of neural folds flanking central neural groove; median hinge point (MHP) anchored to notochord.
Convergence & DLHP – dorsolateral hinge points bring folds toward midline.
Closure – fusion of folds → neural tube; surface ectoderm re-establishes continuity as epidermis.
Closure dynamics:
Initiation near future midbrain; “zips” cranially & caudally.
Terminal openings = cranial (anterior) & caudal (posterior) neuropores; close by \approx\text{day }25\text{ and }27 respectively.
Products of neurulation:
Neural tube → CNS
Neural crest (at dorsal seam) → diverse derivatives
Surface ectoderm → epidermis & appendages
Neural Tube Closure Defects (NTDs)
Among most common congenital anomalies; multifactorial (genetic + environmental e.g., folate deficiency).
Anencephaly: failure of anterior neuropore closure → absent cerebral hemispheres; invariably lethal.
Spina bifida spectrum: failure of caudal closure; severity correlates with exposure of spinal cord/meninges.
Dorsoventral Patterning of the Spinal Cord
Two opposing organizing centers:
Notochord & floor plate (ventral) secrete Sonic Hedgehog (Shh).
Roof plate & surface ectoderm (dorsal) provide BMP/WNT signals (not detailed in transcript but implicit).
Shh acts as a morphogen: concentration gradient specifies ventral neuronal identities (motor neurons vs interneurons).
Experimental evidence: grafted notochord re-specifies ventral identity; removed notochord abolishes ventral types.
Neural Crest (NC)
Origin & EMT
Form at neural plate–epidermis border; delaminate during/after tube closure.
Undergo epithelial-to-mesenchymal transition (EMT) → migrate extensively along defined pathways.
Four major migratory waves (human names): cranial, cardiac, vagal, trunk, sacral.
Derivatives (by region)
Cranial NC: craniofacial cartilage & bone, cranial ganglia (V, VII, IX, X), connective tissue.
Cardiac NC: conotruncal septum of heart, walls of great arteries.
Vagal NC (levels \mathrm{somite}\,1–7): enteric ganglia of foregut & midgut.
Trunk NC: melanocytes, dorsal root ganglia, sympathetic chain, adrenal medulla.
Sacral NC: enteric ganglia of distal colon.
General contributions:
Peripheral nervous system (sensory, sympathetic, parasympathetic neurons; Schwann & satellite glia)
Pigment cells, facial skeleton, ocular tissues, endocrine cells (C-cells of thyroid, chromaffin cells).
Neurocristopathies (Diseases of NC Origin)
Mandibulofacial dysostosis (Treacher Collins syndrome)
Incidence: 1:50,000 live births; autosomal dominant (TCOF1 mutations → Treacle protein deficiency).
Clinical triad: craniofacial bone hypoplasia, middle/outer ear anomalies, dental defects; pathogenesis involves NC cell death.
Hirschsprung’s Disease (Aganglionic megacolon)
Incidence: 1:5,000; mutations in SOX10, EDNRB.
Absence of enteric ganglia in distal bowel → functional obstruction; often with pigmentary/deafness defects (Waardenburg-Shah).
Cranial Placodes Development
Placodes = localized thickenings of cephalic ectoderm; collaborate with NC to build sensory organs & ganglia.
Major sensory placodes & derivatives:
Olfactory placode → olfactory epithelium (smell)
Lens placode → crystalline lens (vision)
Otic placode → inner ear (hearing, balance)
Adenohypophyseal placode (Rathke’s pouch) → anterior pituitary (adenohypophysis) producing endocrine hormones.
Cranial ganglia placodes:
Trigeminal placodes (ophthalmic & maxillomandibular) → sensory neurons of CN V.
Epibranchial placodes (geniculate, petrosal, nodose) → distal sensory ganglia of CN VII, IX, X respectively.
Placode-NC interactions are essential; spatial juxtaposition dictates precise ganglion formation.
Clinical & Practical Notes
Adequate maternal folic acid supplementation reduces risk of NTDs by \approx70\%.
Recognition of NC contribution informs pathophysiology of congenital heart defects & craniofacial syndromes → guides surgical & genetic counseling.
Molecular understanding (e.g., BMP/Shh pathways) provides targets for regenerative medicine & stem-cell based repair of CNS defects.