Last edited: 8/25/2021

8. NEURULATION, VESICULATION, NEURAL CREST CELL MIGRATION

Embryology | Neurulation, Vesiculation, Neural Crest Cell Migration Medical Editor: Gerard Jude Loyola

OUTLINE
By day 18, as the edges of the neural plate move toward
I) NEURULATION one another, it forms the neural folds and the neural
II) VESICULATION groove
III) NEURAL CREST CELL DIFFERENTIATION o Neural groove: U-shaped canal formed by the
IV) FORMATION OF THE SPINAL CORD involution of the neural plate
V) SUPPLEMENTARY IMAGES Cells around the edges of the neural folds specialize and
VI) REVIEW QUESTIONS
differentiate to become neural crest cells
VII) REFERENCES
o Important for the development of different structures
in the peripheral nervous system
I) NEURULATION
(C) NEURAL TUBE FORMATION
Process in which the neural plate involute to form the
neural tube By day 21, edges of the neural fold fuse with one another
→ neural groove completely involutes → forming the
neural tube
Recall (refer to Figure 1):
o Neural tube comes underneath the ectoderm (Figure
The trilaminar disc contains:
2)
o Ectoderm (blue)
o Mesoderm (red) o Neural crest cells (orange) are found by the neural
o Endoderm (blue green) tube
o Notochord is found below the neural tube
The mesodermal-derived cells move through the
o Ectoderm is found above the neural tube
primitive pit forming the notochord
Anterior and posterior neuropores are still open (Figure 3)
(A) NEURAL PLATE FORMATION o As cells continue to proliferate, these neuropore close
o Folate (3-5 mg/d) is important in closing the
neuropores so the cells are able to synthesize DNA
and replicate

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Figure 1. Neurulation showing the formation of the neural plate.

• Notochord releases growth factors (e.g. fibroblast, TGF-

β)
• By day 17, ectodermal cells start to proliferate (called
ectodermal proliferation) → forming the neural plate
• As the neural plate thickens, the embryo allows the
neural plate to involute
o The center of the neural plate pulls down and the
edges roll toward one another
(1) Clinical Significance
(B) NEURAL FOLDS AND NEURAL GROOVE
FORMATION
Figure 2. (Top) Formation of the neural folds, neural groove
and the neural crest cells by day 18. (Bottom) Complete
involution of the neural folds forming the neural tube.
Figure 3. Dorsal view of the neural tube showing an open
neuropores. *Correction: neuropore instead of neutopole.
Lack of folate → neuropores remain open → neural tube
defects
o Anencephaly and encephalocele (when the anterior
neuropore failed to close)
o Spina bifida cystica or occulta (when the posterior
neuropore failed to close)
Complications with spina bifida:
o Arnold-Chiari (Type II) malformation
 Cerebellar tissue and brainstem herniate through
the foramen magnum, often accompanied by
occipital encephalocele and lumbar
myelomeningocele [Moore et al, 2016]
o Dandy Walker syndrome
o Tethered cord syndrome
Complications with encephalocele
o Meckel Gruber syndrome

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  Presents with cystic renal dysplasia, polydactyly, II) VESICULATION
and protrusion of the brain and meningeal tissues
to the occipital area
Neural tube defects are among the most common
congenital anomalies [Moore et al, 2016]
o Primary disturbance, such as teratogenic drugs,
affects cell fates, cell adhesion and mechanism
of neuropore closure resulting in failure of the
neural folds to close and form the neural tube
Figure 6. Vesiculation of the neural tube.
Spina bifida occulta
o Neural tube defect resulting from failure of the Process of forming the brain, brainstem and the spinal
halves of one or more neural arches to fuse in cord from the neural tube
the median plane [Moore et al, 2016]
(A) PRIMARY VESICLES
Spina bifida cystica
o Neural tube defect involving protrusion of the
spinal cord and/or meninges through defects in
the vertebral arches [Moore et al, 2016]

Figure 7. Three primary vesicles from the neural tube.

Neural tube forms the three primary vesicles
Figure 4. (A) Spina bifida occulta; (B-D) Spina bifida o Prosencephalon
cystica [Moore et al, 2016]. o Mesencephalon
o Rhombencephalon
The brain begins to develop during the third week, when
(2) Closure of the Neuropores
the neural plate and tube develop from the
neuroectoderm [Moore et al, 2016]

(B) SECONDARY VESICLES

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Figure 5. Closure of the anterior and posterior neuropores.

By day 24, anterior neuropore closes followed by the Figure 8. Secondary vesicles.
closure of the posterior neuropore by day 26
The complete closure of the neural tube leads to the The primary vesicles proliferate and differentiate to more
development of the central nervous system secondary vesicles:
o Prosencephalon differentiates to:
 Telencephalon
Neural tube differentiates into the CNS [Moore et al, 2016]
Neural crest gives rise to cells that form the ANS • “Looks like a telescope”
and PNS [Moore et al, 2016]  Diencephalon
o Mesencephalon
Table 1. Summary of neurulation. o Rhombencephalon differentiates to:
Day Remarks  Metencephalon
 Myencephalon
15-17 Notochord formation
o The remaining of the neural tube becomes the spinal
Ectodermal proliferation cord
17
Formation of neural plate The secondary vesicles are formed during the fifth week
Formation of the neural groove and neural
18 [Moore et al, 2016]
folds
Complete involution of the neural groove
21 forming the neural tube
Anterior and posterior neuropores still intact
24 Closure of the anterior neuropore
26 Closure of the posterior neuropore

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(C) FORMATION OF THE CNS o Important for catecholamine surge for stress response
o Recall: Preganglionic axons synapse in the
postganglionic motor neuron → release epinephrine
and norepinephrine
Submucosal (Meissner’s) plexus and myenteric
(Auerbach’s) plexus
o Important in the enteric nervous system
o Found within the submucosa and muscularis externa
of the GIT
o Helps regulate the gastrointestinal tract
Dorsal root ganglion
o Pseudounipolar cells located outside the spinal cord
Collateral and chain ganglia
o Preganglionic sympathetic fiber in the lateral gray
horn (T1-L2) project to the chain (paravertebral) or
Figure 9. Primary structures of the CNS formed from the collateral (prevertebral) ganglia
secondary vesicles. Leptomeninges
The secondary vesicles then form the structures of the o Arachnoid + pia mater
CNS: o Surround the brain and spinal cord
o Telencephalon differentiates to: The dura mater is derived from the mesoderm [Ghannam
 Cerebral hemispheres & Al Kharazi, 2021].
o Diencephalon differentiates to: Cranial nerves V, VII, IX and X
 Thalamus, subthalamus, hypothalamus, o Innervates the pharyngeal arches
epithalamus, pineal gland and mammillary bodies o Some sources/books also include CN III and VIII
o Mesencephalon differentiates to: Head and neck
 Midbrain o Neural crest cells also differentiate to different
o Metencephalon becomes the structures of the head and neck
 Pons and cerebellum  Muscles and bones (e.g. malleus, stapes and
o Myelencephalon becomes the incus)
 Medulla
o Spinal cord IV) FORMATION OF THE SPINAL CORD

Table 2. Summary of the differentiation of the primary vesicle,

secondary vesicle to the primary CNS structures.
CNS
Primary Secondary
Structure
Telencephalon Cerebrum
Thalamus
Hypothalamus
(including the Figure 11. Cross-section of the caudal neural tube.
Prosencephalon mammillary The neural tube has three layers (Figure 11):
Diencephalon bodies)
o Marginal zone
Subthalamus
Epithalamus  Outermost layer
(including the  Where neurons and axons start forming
pineal gland) o Mantle zone
 Middle layer
Mesencephalon Mesencephalon Midbrain
 Where neuroblasts are found
Pons o Neuroepithelial zone
Metencephalon
Rhombencephalon Cerebellum  Innermost layer
Myelencephalon Medulla
Cells from the neuroepithelial cells proliferate to become
neuroblasts and eventually, they develop to neurons and
move outward the neural tube
III) NEURAL CREST CELL DIFFERENTIATION
(A) ALAR PLATE AND BASAL PLATE
As cells differentiate and move away from the neural
tube, they make the alar and basal plate
(1) Alar Plate
“Bunny ears” extending dorsally and laterally
Differentiates to become the posterior gray horn (PGH)
o Where sensory neurons are found
Figure 10. Overview of neural crest cell differentiation.
(2) Basal Plate

Neural crest cells migrate and differentiate to different Anterior and lateral extension of the neural tube
structures Differentiates to become the ventral gray horn (VGH)
Melanocytes o Where motor neurons are found
o Found in the skin (3) Neural Tube Remnants
o Produce skin pigments
Enterochromaffin cells in the adrenal medulla Remnants of the neural tube becomes the spinal canal
o Secrete epinephrine (80%) and norepinephrine (20%) containing CSF

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 V) SUPPLEMENTARY IMAGES

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Figure 12. The neural plate folds to form the neural tube. A, Dorsal view shows an embryo of approximately 17 days that was exposed by
removing the amnion. B, Transverse section of the embryo shows the neural plate and early development of the neural groove and neural
folds. C, Dorsal view of an embryo of approximately 22 days shows that the neural folds have fused opposite the fourth to sixth somites
but are spread apart at both ends. D to F, Transverse sections of the embryo at the levels shown in C illustrate formation of the neural
tube and its detachment from the surface ectoderm. Some neuroectodermal cells are not included in the neural tube crest [Moore et al, 2016].

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Figure 13. Schematic illustration shows the embryologic basis of neural tube defects. Meroencephaly (partial absence of brain) results
from defective closure, and meningomyelocele results from defective closure of the caudal neuropore [Moore et al, 2016].

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 Figure 14. Diagrammatic sketches of the brain vesicles indicate the adult derivatives of their walls and cavities. The rostral part of the
third ventricle forms from the cavity of the telencephalon. Most of this ventricle is derived from the cavity of the diencephalon [Moore et al, 2016].
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VI) REVIEW QUESTIONS

All of the following are derived from the neural crest
cells EXCEPT:
a. Ossicles
b. Dura mater
c. Arachnoid mater
d. Submucosal plexus

All of the following differentiate from the

diencephalon EXCEPT:
a. Temporal lobe
b. Pineal gland
c. Mammillary bodies
d. Thalamus

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The sensory neurons from the posterior gray horn is
derived from what structure?
a. Basal plate
b. Alar plate
c. All of the above
d. None of the above

The following statements are TRUE except:

a. Ectodermal cells start to proliferate by day 17.
b. The neural folds and neural groove form by day 18.
c. The neural groove completely involutes to form the
neural tube by day 21.
d. The anterior neuropore closes after the posterior
neuropore, which fuses by day 24.

The following statements are FALSE except:

a. The mantle zone of the neural tube is the middle
layer where neurons and axons start forming.
b. The alar plate is the ventral and lateral extension of
the neural tube.
c. There are five secondary vesicles formed from the
prosencephalon, mesencephalon and
rhombencephalon.
d. Two mg folic acid should be taken by pregnant
women daily to prevent neural tube defects.

CHECK YOUR ANSWERS

VII) REFERENCES
● Moore, K., Persaud, T., & Torchia, M. (2016). The Developing
Human: Clinically Oriented Embryology. Philadelphia: Elsevier.

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