CHAPTER 8

Neurulation
Neurulation Overview:

 Neurulation is a crucial process in embryogenesis that leads to the formation of the neural tube,
the precursor of the central nervous system (CNS), including the brain and spinal cord.

 The development of the CNS begins early in embryonic development, although its functional
development lags behind that of the vascular system.

Primary Neurulation:

 During primary neurulation, the epiblast is induced to form neural ectoderm.

 The initial sign is the formation of a dorsal thickening in the anterior ectoderm, known as the
neural plate.

 The neural plate undergoes shaping, becoming an elongated, keyhole-shaped structure with
broad anterior and narrow posterior regions.

 Neural plate shaping involves convergent extensions, which lead to a net medially directed
movement of cells and contribute to lengthening and narrowing.

 Two lateral elevations called neural folds develop on either side of the neural groove.

 The neural folds elevate, meet in the midline, and eventually fuse to form the neural tube.

 The neural tube is covered by surface ectoderm, which will develop into the future epidermis.

 This process creates the brain and most of the spinal cord.

Secondary Neurulation:

 Secondary neurulation is a different mechanism that occurs in the tail bud region and
contributes to the formation of the lower part of the spinal cord.

 Unlike primary neurulation, secondary neurulation does not involve neural folding.

 In secondary neurulation, the spinal cord initially forms as a solid mass of epithelial cells, and a
central lumen develops secondarily through cavitation.

 The transition from primary to secondary neurulation occurs at the upper sacral level.

Bending of the Neural Plate and Apposition of Neural Folds:

 During primary neurulation, the neural plate undergoes bending at three principal sites:

1. The median hinge point (MHP), overlying the notochord.

2. The paired dorsolateral hinge points (DLHP) at the points of attachment of the surface
ectoderm to the outside of each neural fold.

Primary Neurulation:
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Neurulation
 The median hinge point (MHP), overlying the notochord, is induced by signals from the
notochord and is the primary site of bending in the upper spinal neural plate.

 Convergent extensions and intercalation contribute to the lengthening and narrowing of the
neural plate.

 Neural folds develop on both sides of the neural groove as dorsal elevations.

 Actin microfilaments in neuroepithelial cells play a crucial role, especially in anterior

neurulation, as disruption of the actin cytoskeleton can impact neural tube closure.

 Cellular protrusions extend from apical cells of neural folds during their approach, allowing
initial cell-cell recognition and adhesion.

Fusion of Neural Folds:

 Fusion of neural folds initiates in the cervical region and progresses anteriorly and posteriorly.

 Cell-surface glycoconjugates mediate this fusion process.

 The neural tube becomes separated from the overlying ectodermal sheet as fusion progresses.

 The anterior and posterior neuropores are temporary openings of the neural tube that
eventually close, marking the completion of neurulation.

 During neurulation, the neuroepithelium is entirely proliferative, and neuronal differentiation

occurs after neural tube closure.

Apoptosis During Neurulation:

 Cell proliferation during neurulation is accompanied by a controlled degree of apoptosis in the

neuroepithelium.

 The rate of apoptosis is finely regulated, and both excessive and reduced apoptosis can disrupt
neural tube closure.

 Apoptosis at the tips of the neural folds is essential for dorsal midline remodeling and separation
between neuroepithelium and surface ectoderm.

Neural Crest Formation:

 Neural crest cells are formed from the lateral border or crest of the neuroepithelium.

 Their formation involves an epithelio-mesenchymal transition as they migrate into the

underlying mesoderm.

 Neural crest cell induction is influenced by interactions between neural and surface ectoderm,
possibly mediated by BMP4, BMP7, and Wnt.
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Neurulation
 Slug, a zinc finger transcription factor, characterizes neural crest cells that break away from the
embryonic cell layer to migrate.

 Migration of neural crest cells can occur before or after neural tube closure, depending on the
region.

 Neural crest cells contribute to a diverse range of tissues, including craniofacial skeleton, cranial
ganglia, Schwann cells, and melanocytes.

 Their migration involves changing from neuroepithelial cell properties to mesenchymal cell
properties, including penetrating the basal lamina underlying neural epithelium.

Derivative Category Specific Derivatives

Sensory Nervous System - Ganglia of trigeminal nerve (V)

- Ganglia of facial nerve (VII)

- Superior ganglion of glossopharyngeal nerve

- Jugular ganglion of vagus nerve

Autonomic Nervous System - Parasympathetic ganglia:

- Ciliary ganglia

- Ethmoidal ganglia

- Sphenopalatine ganglia

- Submandibular ganglia

- Visceral ganglia

Supporting Cells - Satellite cells of sensory ganglia

- Schwann cells of peripheral nerves

- Leptomeninges of prosencephalon

- Leptomeninges of part of the mesencephalon

Endocrine Cells - Carotid body

- Parafollicular cells of the thyroid

Pigment Cells - Melanocytes

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Neurulation
Derivative Category Specific Derivatives

Mesectodermal Cells - Cranial vault (including squamosum and part of os frontale)

- Nasal and orbital bones

- Part of the otic capsule

- Palate

- Maxilla

- Visceral cartilage

- Part of external ear cartilage

Connective Tissue - Dermis and adipocytes of the skin

- Cornea of the eye

- Odontoblasts

- Stromal cells of glands (thyroid, parathyroid, thymus, salivary, lachrymal)

- Outflow tract of the heart

- Cardiac semilunar valves

- Walls of the aorta and aortic-arch derived arteries

Muscle - Ciliary muscle

- Dermal smooth muscles

- Vascular smooth muscle

Epithelial-Mesenchymal Transition in Neural Crest Cells:

One significant change that accompanies the epithelial-mesenchymal transition of neural crest cells is
the loss of cell adhesiveness due to the loss of adhesion molecules (CAMs) characteristic of the neural
tube. Examples of these adhesion molecules include N-CAM and N-cadherin.

Migration of Neural Crest Cells:

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Neurulation
After leaving the neuroepithelium, neural crest cells migrate along well-defined pathways through an
environment that is relatively poor in cells but rich in extracellular matrix molecules. The migration
process is influenced by both intrinsic properties of the cells and the environment they encounter.

Migration is supported by components of the extracellular matrix, such as fibronectin, laminin, and type
IV collagen, found in the basal lamina. Attachment to and migration over these substrate molecules are
mediated by integrins present on the migrating neural crest cells. On the other hand, molecules like
chondroitin sulfate proteoglycans can inhibit the migration of neural crest cells.

Anterior Neural Crest:

Neural crest cells in the developing head and trunk follow different migration pathways. The anterior
neural crest is a major component of the developing cephalic end of the embryo. These cells leave the
nascent neurotube well before fusion of the neural folds and migrate through the anterior mesenchyme
to reach their final destinations in the developing head. The paths they take are controlled by local
differences in the extracellular matrix.

The origins of the neural crest cells in the anterior rhombencephalon significantly influence their
ultimate destination within the pharyngeal arches. Neural crest cells from different rhombomeres
migrate into specific pharyngeal arches. For example, cells from rhombomeres 1 and 2 migrate into the
first pharyngeal arch, while those from rhombomere 4 migrate into the second arch, and so on. Gene
expression patterns, specifically related to the HoxB gene complex, correlate with these migration
patterns and influence differentiation.

It was long assumed that anterior neural crest cells were pre-programmed with distinct morphogenetic
instructions before leaving the neural tube. However, recent experiments have shown that
environmental factors encountered during migration play a decisive role in determining the fate and
differentiation of these cells.

Derivatives of Anterior Neural

Crest Cells Components

Sensory Nervous System Spinal ganglia

Ganglia of the sympathetic chain, coeliac and mesenteric ganglia, visceral and
Autonomic Nervous System pelvic plexuses, Schwann cells of peripheral nerves

Satellite cells of sensory

ganglia Enteric glial cells

Endocrine Cells Adrenal medulla, neurosecretory cells of the heart and lung

Pigment Cells Melanocytes

Mesectodermal Cells None

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Neurulation
Derivatives of Anterior Neural
Crest Cells Components

Connective Tissue None

Muscle None

This table summarizes the major derivatives of anterior neural crest cells and the components they
differentiate into, including sensory and autonomic nervous system elements, endocrine cells, pigment
cells, and more.

Circumpharyngeal Neural Crest:

 Originates in the posterior rhombencephalic region and lower part of the pharynx.

 Migration towards:

 Gut: Parasympathetic vagal neural crest cells (from somites 1 to 7) become precursors
of parasympathetic neurons in the digestive tract, populating the entire length of the
gut and forming the submucosal and myenteric plexuses.

 Heart: Cardiac neural crest cells (originating from the anterior rhombenecephalon to
somite 5) contribute to the cardiac outflow tract, semilunar valves, proximal coronary
arteries, and can differentiate into Schwann cells of cranial nerves.

 Association with other organs: Some cardiac neural crest cells associate with the thymus,
parathyroid, and thyroid glands, contributing to organ development.

 Abnormalities: Deficiencies in cardiac neural crest cells can lead to conditions like DiGeorge
syndrome, characterized by issues in thymus, thyroid, parathyroid, cardiovascular defects, and
aortic arch abnormalities.

 Migration to pharynx: Circumpharyngeal neural crest cells also migrate ventrally to the pharynx,
accompanying somite-derived myoblasts involved in forming intrinsic muscles of the tongue and
hypopharyngeal muscles, as well as contributing to the connective tissue in these muscles.

 Consequences of disturbance: Disturbances in this region can result in cardiac septal defects
(aorticopulmonary septum) and glandular and craniofacial malformations.

Trunk Neural Crest:

 Extends from the sixth somite to the most posterior somites in the trunk.

 Three main migratory pathways:

1. Dorsolateral pathway between ectoderm and somites, leading to dispersion and entry
into ectoderm as pigment cells (melanocytes).
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Neurulation
2. Ventromedial pathway involves migration into space between somites and neural tube,
leading to the formation of sympathoadrenal lineage, contributing to the sympathetic
nervous system, adrenal medulla, and other related structures.

3. Ventrolateral pathway enters anterior halves of somites, forming sensory or spinal

ganglia.

 Sympathoadrenal lineage differentiation: Involves committed sympathoadrenal progenitor cells

leading to adrenal chromaffin cells, small intensely fluorescent cells, adrenergic sympathetic
neurons, and a small population of cholinergic sympathetic neurons.

 Influences on differentiation: Differentiation into adrenal chromaffin cells or sympathetic

neurons depends on the local environment and factors like FGF, NGF, and glucocorticoids.

 Enteric nervous system: Neural crest cells populate the entire gut, forming the enteric nervous
system, which operates independently from the central nervous system, regulating bowel reflex
activity.

 Developmental flexibility: Neural crest cells retain developmental flexibility, and their
differentiation can be influenced by the local environment.

 Trunk neural crest derivatives summarized in Table 8-2.

Phylogenetic Origin of the Neural Crest:

 The neural crest is a characteristic feature of vertebrates.

 Its derivatives are considered homologous to epidermal and visceral nerve plexuses in non-
vertebrates.

 The evolution of the neural crest is associated with the centralization of the nervous system and
the development of special sense organs, locomotor structures, and protective skeletal
elements.

 Neural crest cells have two primary developmental fates: forming ganglionic elements and
supporting structures of the peripheral nervous system and differentiating into mesenchyme or
ectomesenchyme.

 The developmental fate of neural crest cells varies depending on their level of origin: anterior
neural crest (anterior to somite 7) can form neurons and ectomesenchyme, while trunk neural
crest (posterior to somite 7) typically forms neural structures and somites, with less
ectomesenchymal differentiation under physiological conditions.

Summary of Neurulation and Neural Crest Development:

 Primary neurulation: Formation of the neural plate, neural folds, neural groove, and neural tube,
with closure of the anterior and posterior neuropores.
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Neurulation
 Secondary neurulation: Development of the posterior portion of the neural tube by forming a
lumen in the solid neural cord.

 Neural crest: Cells at the lateral border of the neuroepithelium undergo an epithelial-to-
mesenchymal transition and actively migrate into the underlying mesoderm.

 Neural crest's pluripotent nature: Considered a pluripotent stem cell population contributing to
various neural and non-neural organ systems.

 Differentiation of neural crest cells: They differentiate into neurons, peripheral nervous system
glial cells, melanocytes, adrenal medullary cells, cartilage, bone, dentin, dermal fibroblasts,
smooth muscle cells, and more.

 Migration paths in the trunk: Dorsolateral pathway for melanocytes, ventral pathway for
sympatho-adrenal lineage cells, and ventrolateral pathway through somites for sensory ganglia
formation.

 Trunk neural crest and skeletal elements: In contrast to cranial and circumpharyngeal neural
crest cells, trunk neural crest cells do not typically differentiate into skeletal elements.