Development of the Nervous System Study Notes

Molecular Regulation of Nervous System Development

• Spinal Cord Regulation:

  • Differentiation of the dorsal and ventral regions depends on a gradient of signaling molecules.
  • TGF-Beta Family: Secreted by the dorsal neural tube (overlying ectoderm).
  • Sonic Hedgehog (SHH): Secreted by the floor plate and the notochord.
  • Bone Morphogenetic Proteins (BMP 4 & 7): Secreted by the non-neural ectoderm to establish a cascade of $TGF-\beta$ proteins that control the timing and spatial distribution of differentiation.
  • Transcription Factors: Overlapping concentrations of $TGF-\beta$ and $SHH$ activate transcription factors regulating sensory (dorsal) and motor (ventral) neurons.
  • PAX 3 and 7 / MSX 1 and 2: Initially expressed throughout the neural plate. $SHH$ represses them in the ventral half (floor/basal plates), while $BMPs$ upregulate and maintain them in the dorsal half (roof/alar plates).
  • PAX 6: Expressed throughout the neural ectoderm as neural folds elevate and close.

• Brain Regulation:

  • Homeobox Genes: Provide signals for the segregation of the brain into the forebrain, midbrain, and hindbrain.
  • Retinoic Acid: Regulates homeobox gene expression and craniocaudal patterning.
  • FGF-8: A key signaling molecule inducing subsequent gene expression for differentiation.
  • FOXG1: Transcription factor regulating cerebral hemisphere development and specification within the forebrain.
  • BMP 4 & 7: Control lateral patterning.
  • SHH: Induces the $NKX2.1$ gene for hypothalamus development.
  • WNT1: Induced by $FGF-8$ to regulate regions of the cerebellum.
  • Engrailed 1 and 2 (EN1 and EN2): Secreted in gradients near the isthmus; $EN1$ regulates the dorsal midbrain, and both participate in cerebellum formation.

Early Development and Neurulation

• Origin: The nervous system is ectodermal in origin.
• Timeline: Development begins early in the $3rd$ week from the neural plate, a slipper-shaped thickening between the primitive knot and the prechordal plate.
• Process of Neurulation:
  • Day 18: The neural plate invaginates along its central axis, forming the neural groove with neural folds on each side.
  • Fusion: Neural folds approach and fuse to form the neural tube. This begins in the region of the $4th$ to $6th$ somites (cervical region) and proceeds cranially and caudally.
  • Neuropores: Large openings at the ends.
  • Cranial Neuropore: Communicates with the amniotic cavity; closure is bi-directional and finalizes on Day $25$.
  • Caudal Neuropore: Final closure occurs on Day $27$.
• Vesicle Formation: The brain shows three primary dilatations once the tube closes:
  1. Forebrain (Prosencephalon).
  2. Midbrain (Mesencephalon).
  3. Hindbrain (Rhombencephalon).
• Neural Canal: Becomes the ventricular system of the brain and the central canal of the spinal cord.

Neural Crest Formation and Derivatives

• Formation: As neural folds fuse, lateral neuroectodermal cells lose epithelial affinity and undergo a mesenchymal transition. They dissociate and migrate dorsolaterally to form the neural crest.
• Differentiation Derivatives:
  1. Ganglia (spinal, autonomic, and cranial).
  2. Neurolemma (Schwann) cells and satellite cells.
  3. Meninges (pia and arachnoid).
  4. Melanocytes.
  5. Suprarenal medulla.
  6. Connective tissue, skeletal, and muscular components of the head and pharyngeal arches.
  7. Heart cushions.
  8. Odontoblasts.
  9. Chromaffin cells in paraganglia.
  10. Eye structures (cornea, pupillary muscles, vitreous body).

Histogenesis of the Nervous System

• Neural Tube Wall Layers:
  • Neuroepithelial Layer: Pseudostratified columnar cells lining the lumen; they divide rapidly.
  • Mantle Layer: Formed by primordial neurons (neuroblasts) migrating from the neuroepithelium. This layer becomes the gray matter.
  • Marginal Layer: The outermost layer containing nerve fibers emerging from neuroblasts. It becomes the white matter as fibers are myelinated.
• Nerve Cell (Neuron) Development:
  • Neuroblasts are initially apolar and rounded.
  • They become bipolar neuroblasts with two processes.
  • One process elongates into a primitive axon; the other arborizes into a primitive dendrite, forming a multipolar neuroblast (neuron).
• Glial Cell Development:
  • Glioblasts: Produced by neuroepithelial cells after neuroblast production stops. They migrate to mantle/marginal layers.
  • Astrocytes: Differentiate into protoplasmic astrocytes (gray matter) and fibrous astrocytes (white matter).
  • Oligodendrocytes: Derived from oligodendroblasts; form myelin sheaths in the CNS.
  • Microglia: Derived from mesenchyme; phagocytic in nature.
  • Ependymal Cells: Simple columnar partially ciliated epithelium lining the central canal.

Development of the Spinal Cord

• Structural Architecture:
  • Sulcus Limitans: A longitudinal groove separating the dorsal and ventral halves of the lateral walls.
  • Basal Plates: Ventral thickenings containing motor and autonomic neurons (ventral/lateral gray horns).
  • Alar Plates: Dorsal thickenings containing sensory neurons (dorsal gray horns).
  • Roof and Floor Plates: Midline portions that serve as crossing pathways for fibers; they do not contain neuroblasts.
• Physical Development:
  • As basal plates grow, they form the anterior median fissure.
  • Alar plates extend medially to form the posterior median septum.
• Positional Changes (Recession):
  • $3$ months: The cord extends the full length of the vertebral canal.
  • $6$ months: The cord ends at $S1$.
  • Newborn: The cord ends at $L3$.
  • Adult: The cord ends at the lower border of $L1$.
  • Structures: Filum terminale (pia mater fibrous thread) indicates the line of regression. Cauda equina refers to the nerve roots below the conus medullaris.
• Myelination:
  • PNS: Conducted by Schwann cells coiling around axons.
  • CNS: Conducted by oligodendroglia.
  • Motor roots myelinate before sensory roots.
  • Begins in the $4th$ month of life; continues until $20$ years for some cerebral fibers.

Spinal Cord Anomalies

• Incidence: $1$ in $1000$.
• Major Causes: Folic acid deficiency, Hypervitaminosis A, Valproic acid, and temperature extremes.
• Diagnosis: Ultrasonography and increased alpha-fetoprotein ($AFP$) in maternal serum/amniotic fluid.
• Types of Spina Bifida:
  • Spina Bifida Occulta: Defect in vertebral arches covered by skin (often marked by a tuft of hair). Occurs in $10\%$ of people, usually at $L5$ or $S1$.
  • Spinal Dermal Sinus: Skin dimple at the sacral region marking the caudal neuropore closure.
  • Spina Bifida Cystica: Protrusion of meninges/cord through vertebral defects.
  • Meningocele: Protrusion contains only meninges and CSF.
  • Meningomyelocele: Protrusion contains spinal cord and/or nerve roots; involves neurological deficits/paralysis.
  • Myeloschisis (Rachischisis): Failed fusion of neural folds; the cord is an open, flattened mass.
  • Syringomyelocele: Gross dilation of the central canal.

Brain Development and Vesicles

• Primary Brain Vesicles (3rd week):
  • Prosencephalon (Forebrain).
  • Mesencephalon (Midbrain).
  • Rhombencephalon (Hindbrain).
• Secondary Brain Vesicles (5th week):
  • Prosencephalon divides into Telencephalon (cerebrum) and Diencephalon (thalamus).
  • Mesencephalon remains the same.
  • Rhombencephalon divides into Metencephalon (pons/cerebellum) and Myelencephalon (medulla).
• Brain Flexures:
  1. Midbrain Flexure: Ventrally curved in the midbrain.
  2. Cervical Flexure: Ventrally curved between hindbrain and spinal cord.
  3. Pontine Flexure: Dorsally curved in the metencephalon region.
  4. Forebrain Flexure: Dorsally curved in the forebrain.

The Hindbrain (Rhombencephalon)

• Myelencephalon (Medulla Oblongata):
  • The caudal "closed medulla" resembles the spinal cord.
  • The rostral "open medulla" is wide; pontine flexure thins the roof plate into the tela choroidea.
  • Basal Plate Columns (Motor): GSE (Hypoglossal nucleus), SVE (Nucleus ambiguus for arches), GVE (Dorsal motor nucleus of Vagus, inferior salivary nucleus).
  • Alar Plate Columns (Sensory): SSA (Vestibulocochlear), GSA (Trigeminal face sensation), SVA (Taste), GVA (Visceral sense to nucleus solitarius).
• Metencephalon (Pons and Cerebellum):
  • Pons: Acts as a bridge for fibers; contains pontine nuclei derived from alar plates.
  • Cerebellum: Develops from rhombic lips (thickenings of alar plates).
  • Structure: Vermis (midline) and Hemispheres (lateral expansions).
  • Lobes: Flocculonodular (primitive/balance), Anterior (muscle tone), Posterior (coordination).
  • Cells: Purkinje cells and the external granular layer.

The Midbrain (Mesencephalon)

• Tectum (Roof): Alar plate neuroblasts form the superior and inferior colliculi (visual/auditory reflexes).
• Tegmentum: Basal plate neuroblasts form the red nucleus, reticular nuclei, and substantia nigra.
• Motor Nuclei: GSE (Oculomotor $III$ and Trochlear $IV$) and GVE (Edinger-Westphal nucleus).
• Cerebral Peduncles (Crura Cerebri): Descending fiber pathways (corticospinal, etc.) in the ventral marginal layer.

The Forebrain (Prosencephalon)

• Diencephalon:
  • Consists of two alar plates; lacks basal/floor plates.
  • Thalamus: Two sides fuse at the interthalamic adhesion.
  • Hypothalamus: Regulates homeostasis, endocrine activity, and visceral functions. Formed by mammillary bodies ventrally.
  • Epithalamus: Develops into the pineal body (epiphysis), which secretes melatonin, and the habenular complex.
  • Pituitary: Formed by the union of Rathke’s pouch (oral ectoderm) and the neurohypophysial diverticulum (neuroectoderm).
• Telencephalon:
  • Consists of two cerebral vesicles (hemispheres) and the lamina terminalis.
  • Basal Ganglia: Corpus striatum appears in the 6th week; divided by the internal capsule into the caudate and lentiform nuclei.
  • Cerebral Cortex (Pallium):
  • Histogenesis occurs via waves of migration (inside-out sequence).
  • Six laminae are present by the $8th$ month.
  • Areas: Archicortex (hippocampus), Paleocortex (olfactory), Neocortex (dominant).

White Matter and Commissures

• Fiber Types:
  • Association Fibers: Connect areas within the same hemisphere (e.g., arcuate bundle, longitudinal bundles).
  • Commissure Fibers: Cross the midline.
  • Corpus Callosum: Largest; connects neocortical areas ($4th$ month).
  • Anterior Commissure: Connects olfactory bulbs.
  • Posterior Commissure: Inferior to the pineal body.
  • Projection Fibers: Connect cortex to lower centers (e.g., internal capsule).
• Timetable of Tracts:
  • End of 1st Month: Spinal trigeminal tract.
  • End of 2nd Month: Thalamic peduncles, internal capsule.
  • 3rd Month: Anterior commissure.
  • 4th Month: Corpus callosum.
  • 5th Month: Pyramidal fibers.

Congenital Brain Malformations

• General Causes: Down syndrome, alcohol (teratogens), Rubella, irradiation, or birth trauma.
• Cranium Bifidum: Occipital bone defect; can result in meningocele or meningoencephalocele.
• Anencephaly (Meroanencephaly): Failed closure of the rostral neuropore; skull vault/brain largely missing. Associated with polyhydramnios.
• Microcephaly: Small brain; results in impaired mental development.
• Hydrocephalus: Accumulation of CSF.
  • Obstructive: Often via aqueductal stenosis (aqueduct of Sylvius).
  • Communicating: Blockage in subarachnoid space or malformation of arachnoid villi.
• Holoprosencephaly: Failure of the prosencephalon to divide; single holoventricle. Linked to $SHH$ mutations and maternal diabetes.
• Arnold-Chiari Malformation: Herniation of the cerebellum/medulla through the foramen magnum.
• Dandy-Walker Syndrome: Agenesis of the cerebellar vermis and atresia of 4th ventricle apertures.

Peripheral and Autonomic Nervous Systems

• Spinal Ganglia: Derived from neural crest cells; pseudounipolar neurons.
• Autonomic Nervous System:
  • SNS: Neural crest cells migrate to form the paravertebral chain (sympathetic trunk) and prevertebral ganglia (celiac/mesenteric). Chromaffin cells form the suprarenal medulla.
  • PSNS: Craniosacral origin ($III, VII, IX, X$ and $S2-S4$). Terminal ganglia located in or near organ walls.
• Hirschsprung Disease (Congenital Aganglionic Megacolon):
  • Incidence: $1$ in $5000$ (Male $4:1$ Female).
  • Mechanism: Failure of neural crest cell migration into the large colon wall, resulting in a lack of parasympathetic ganglia. This leads to a constricted paralyzed segment and proximal dilation.