EMBRYOLOGY OF THE CENTRAL NERVOUS SYSTEM

Early embryonic development (1, 2, 6)

• During first four days post-ovulation (POD 1-4), human embryo undergoes approximately 5 rounds of cell division to produce 32-cell morula (figure 1a)
• inner cell mass will give rise to embryo proper
• surrounding trophoblast cells give rise to placental tissues
• Inner cell mass differentiates into two layers
• Epiblast dorsally
• Hypoblast ventrally
• Amnionic and yolk sac cavities develop above (dorsal to) and below (ventral to) the suspended inner cell mass by POD 12 (figure 1b)
• Cranial end of embryo visible by POD 13 with development of prochordal plate, a thickening of cranial end of embryo (figure 1c)

Gastrulation

• Primitive streak (PS) develops at caudal end of embryo by POD 13

1. PS elongates toward cranial end of embryo between POD 13-16
2. Reaches its full length by POD 16, covering midline in caudal half of embryo
3. PS begins to regress beyond POD 16 back toward the caudal embryo, ends up as caudal cell mass by POD 28
4. During elongation, prospective endodermal cells move toward the midline and invaginate (ingress) through the cranial half of the primitive groove (extra-embryonic cells ingress through the caudal half), displacing hypoblast cells laterally and replacing them beneath epiblast to form definitive endoderm (giving rise to respiratory and gastrointestinal epithelium)
5. During regression mesodermal cells ingress through primitive streak to form somitic (giving rise to somites), intermediate (giving rise to renal system) and somatopleural (giving rise to limbs) mesoderm on either side of the PS between epiblast and newly formed endoderm
6. Remaining cells of epiblast spread out and differentiate to form neuroectoderm (central nervous system) and cutaneous ectoderm (skin)
7. Gastrulation converts the embryo from a two layered structure having epiblast and hypoblast, to a three-layered structure containing ectoderm, mesoderm, and endoderm (figure 2a)

• Hensen’s node represents the cranial terminus of the PS, the primitive pit the cranial terminus of the primitive groove

1. During PS elongation endoderm ingresses through the primitive pit
2. During PS regression, prospective notochordal cells ingress through the primitive pit, between the newly formed endoderm and neuroectoderm in the midline to form the notochordal canal (figure 2b)

• Newly formed notochordal canal (POD 16) is a rod composed of cells radially arranged about a central lumen (Figure 3a); the cells are contiguous with Hensen’s node, and the lumen is contiguous with the amnion through the primitive pit

1. Notochordal canal fuses (figure 3b) with underlying endoderm (intercalation) for approximately 3 days, during which amnion is contiguous, via the lumen of the notochordal canal, with the yolk sac; this communication is called the primitive neurenteric canal.
2. By POD 25 the notochordal process has reformed, separating from the endoderm (excalation), and becoming the true notochord, and the primitive neurenteric canal is obliterated (figure 3c)

Primary Neurulation (1, 2, 6, 10)

• Primary neurulation forms brain, and spinal cord as far caudal as the second sacral level (S2)
• Primary neurulation occurs between POD 17-27, resulting in the formation of a neural tube and separation of cutaneous from neuroectoderm (figure 4)
• Primary neurulation is comprised of two distinct processes: neural plate shaping and neural plate bending
• Neural plate shaping is due to both directed cell division as well as changes in the shape of neural plate cells (converting neural plate cells from cuboidal to columnar through the action of microtubules)
  
  Narrows and elongates the neural plate to an area immediately cranial to Hensen’s node (forming the brain) and flanking either side of the PS (forming the spinal cord)
• Neural plate bending involves four separate actions

1. Formation of a midline furrow, the neural groove (or median hingepoint) directly overlying the notochord (and induced by the notochord)
2. Elevation of the laterally paired neural folds surrounding the neural groove
3. Formation of bilaterally paired lateral hingepoints and convergence of the neural folds toward the midline
4. Fusion of the neural folds to one another, and separation of the cutaneous from neuroectoderm (dysjunction)

• Neural crest cells lie near the junction of cutaneous and neuroectoderm and are destined to form a variety of tissues including:

1. Branchial arch derivatives
2. Dorsal roots and dorsal root ganglia
3. Autonomic ganglia (both sympathetic and parasympathetic)
4. Adrenal medulla (adrenergic cells)

• Neural fold fusion occurs first near the cervicomedullary junction, and proceeds both cranial and caudal from this point
• Secondary waves of closure may occur at other levels of the neuraxis as well
• Points where waves of closure meet are called neuropores
• The last two points of closure are the anterior neuropore (represented by the lamina terminalis (which is the posterior portion of the commissural plate) at POD 24, and the caudal neuropore (opposite spinal cord level S2) at POD 26

Secondary Neurulation (2, 8, 9)

• Secondary neurulation begins on POD 27 caudal to the posterior neuropore, forming the spinal cord caudal to S2 as well as the future filum terminale from the caudal cell mass (figure 5)
• Secondary neurulation occurs in the presence of an intact cutaneous ectoderm overlying the caudal cell mass
• Secondary neurulation is less well organized than primary neurulation
• Multiple small tubules are formed, composed of cells radially arranged about a central lumen
• Smaller tubules coalesce into larger tubules independent of the neural tube formed from primary neurulation (primary neural tube)
• Eventually the caudal neural tube borne from the coalescence of these tubules fuses with the primary neural tube
• Secondary neurulation is species-specific; the above scheme is described in avian embryos, but it is not clear whether this occurs in humans

Ascent of the Conus Medullaris (3, 11)

• The tip of the conus medullaris (CM) originally lies opposite the embryonic coccygeal spinal segments with nerve roots exiting directly opposite their vertebral levels
• Conus medullaris appears to ascend, relative to the adjacent spine, beyond POD 17
• Between POD 27 and 54, the caudal end of the newly formed neural tube undergoes retrogressive differentiation during which it becomes thinner, is less well developed, and eventually contains no marginal zone and only a rudimentary mantle zone
• Beyond POD 54, differential growth of the vertebral column relative to the spinal cord result in a progressive disparity between the spinal cord and vertebral levels, such that nerve roots exiting a particular spinal cord level have to travel farther caudal within the thecal sac toward their eventual exit foraminae
• The CM appears therefore to lie opposite progressively more cranial vertebral levels throughout the remainder of embryogenesis
• The CM occupies its ‘adult level’, most commonly opposite or cranial to the L1-L2 disc space, by birth or within 2 months post-natal
• Any CM lying caudal to the mid-body of L2 is considered abnormally low (95% confidence limits) and therefore potentially tethered

Formation of Primary and Secondary Neural Vesicles and Flexures (4, 6, 7)

• Neural tube divides into three morphologically and histochemically distinct primary vesicles during fourth embryonic week:
• Prosencephalon (forebrain)
• Mesencephalon (midbrain)
• Rhombencephalon (hindbrain)
• Five secondary vesicles develop during the fifth week
• Prosencephalon divides into two secondary vesicles
• Telencephalon (cerebrum, basal ganglia)
• Diencephalon (hypothalamus, thalamus, epithalamus, neural retina, pineal body)
• Mesencephalon remains unchanged and gives rise to tectum (superior and inferior colliculi), midbrain tegmentum, and cerebral peduncles c.R
• Rhombencephalon divides into two secondary vesicles
• Metencephalon (pons, cerebellum)
• Myelencephalon (medulla)
• Bending of the neuraxis (primary flexures) occurs during the fourth week
• Mesencephalic flexure occurs at the level of the mesencephalon/midbrain
• Cervical flexure occurs at the junction of metencephalon and spinal cord
• Both flexures are concave dorsally
• 4.Pontine flexure occurs during fifth week between mesencephalic and cervical flexures and is concave ventrally. Roof of mesencephalon is thinned as a result of the pontine flexure and produces roof of IV ventricle

Development of Alar and Basal Plates; Formation of Cranial Nerve Nuclei (4, 5)

• Early post-neurulation neural tube develops into dorsal and ventral halves - the alar and basal plates respectively - separated by the sulcus limitans
• Cells within the basal plate develop into efferent neurons
• Cells within the alar plate develop into afferent and interneurons
• Within the spinal cord, the alar plate gives rise to Rexed’s laminae I-IV whereas the basal plate gives rise to Rexed’s laminae VII-X
• Within the brainstem, further developments within the alar and basal plates produce a complex of cranial nerve nuclei that are understandable from an embryological standpoint. In particular, the pontine flexure and the resultant thinning of the rhombencephalic roof splays the rhombencephalon so that the alar plate comes to lie dorsolateral to the basal plate:
• The alar plate further develops general sensory afferents (GSA) innervating the skin, special sensory afferents (SSA) innervating the branchial arch derivatives, and visceral sensory afferents (VSA) innervating the respiratory, cardiac, and gastrointestinal systems
• The basal plate also further develops general motor efferents (GME) innervating somatic muscles, special motor efferents (SME) innervating branchial arch derived muscles, and visceral motor efferents (VME) innervating autonomic (respiratory, cardiac, and gastrointestinal system) muscles
• In general, each type of afferent and efferent is organized along loosely defined columns from dorso-medial to ventro-lateral
• Medial-to-Lateral: GSA > SSA > VSA
• Medial-to-Lateral: GME > SME > VME d.Each cranial nerve is comprised of axons derived from one or more of these sensory and motor groups (Table 1)
• The cerebellum is a greatly expanded outgrowth of the alar plate of the metencephalon that performs integrative (interneuron) functions
• Cranial to the midbrain only the alar plate exists, its derivatives giving rise to the sensory and integrative functions of the thalamus, hypothalamus, basal ganglia and telencephalon (both hypothalamic and pyramidal cells are technically considered interneurons since they innervate other effector cells – the ventral horn motoneurons in the case of the cortical pyramidal cells, and the humeral cells of the pituitary gland in the case of the hypothalamic neurons)

Neuronal Migration - Formation of the Spinal Cord, Brainstem, Cerebellum, Deep Nuclei and Cortex (5)

• In both the spinal cord and brain, neuroblasts (primitive neurons) proliferate within the subependymal zone of the neural tube.
• As neuroblasts mature their progeny migrate from the subependymal zone to their final destinations
• The exact organization of this migration depends upon the location within the neuraxis:
• In the spinal cord cells remain near the subependymal zone to form the central gray matter of the spinal cord and extend axonal processes toward the periphery of the spinal cord. The surrounding spinal cord white matter is comprised of local and ascending white matter tracts generated within the spinal cord gray matter, and descending tracts from supranuclear sources.
• In the brainstem cells migrate toward, and differentiate into, various nuclei derived from the alar and basal plate neurons; intermixture of axonal processes with nuclei gives the peculiar brainstem structure
• Formation of the cerebellum occurs from two distinct subependymal germinal zones
• A germinal zone in the roof of the IV ventricle produces cells that migrate peripherally to form the cerebellar nuclei and Purkinje layer.
• A second germinal zone in the rhombic lips lateral to the IV ventricle form the basket and stellate cells. These cells migrate circumferentially around the surface of the cerebellum to form the external granular layer. Later, daughter cells in the external granular layer migrate inward through the Purkinje cells and form the internal granular layer. Migration takes place along Bergman glia that guide neurons to their final destinations.
• Thalamus/hypothalamus and globus pallidus form from migration of cells in the diencephalic germinal zone along the walls of the third ventricle. The caudate, putamen and amygdala form from similar germinal zones in the ganglionic eminence of the lateral ventricle.
• Formation of the cerebral cortex involves five processes

1. Cells in the ependymal zone migrate to form the marginal later (layer I) of the cortex
2. A subventricular (germinal matrix) zone develops immediately adjacent to the ventricular ependyma
3. Cells from the germinal matrix migrate to the cortex in an inside out pattern with layer 6 neurons forming first and successive waves of migration forming more superficial layers
4. Locally multiplying presumably glial cells populate the cortex
5. Remaining non-migrating germinal matrix produces ependymal cells.

Suggested Reading

References

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