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Flashcards in Neuro embryology Deck (15):

Explain general processes of neural tube formation in initiation of nervous system development

Neural tube formation (neurulation) occurs with induction of ectoderm by secretion of factors from the underlying notochord (a midline rod of mesoderm) so that developing neuroectoderm cells organize in the midline as a thickening called the neural plate. (Recall that notochord eventually
forms the nucleus pulposus of intervertebral discs in the adult.)

The neural tube wall is made up of neuroepithelial cells that proliferate and differentiate to form the neurons and neuroglia of the CNS.

The main signal that triggers the development of the ventral part of the neural tube is the production of sonic hedgehog (SHH) by the notochord and subsequent differentiate of ventral cells of the neural tube. Signals responsible for development of the dorsal part of the neural tube are produced by surface ectoderm (developing skin epidermis) include many of the TGF-beta family. The sulcus limitans separates the developing neural tube into dorsal and ventral halves throughout the developing brainstem and spinal cord.

Proliferation of neuroectoderm cells in the neural plate results in “buckling”/folding of tissue to form a depression called the neural groove
with raised bilateral neural folds. With further proliferation (and more buckling of a deepening neural
groove), the edges of the neural folds approximate and fuse in the dorsal midline to form the neural
tube, which detaches from the epidermis-forming surface ectoderm. The caudal end of the neural
plate and tube, which is narrower than the cranial end, will become the spinal cord, whereas the wider, cranial end will become the brain.
- Fusion to form the neural tube begins in the cervical region and occurs as a bi-directional “zipper” that
proceeds cranially and caudally. The open (unfused) ends of the neural tube are called neuropores. The final step of primary neurulation is neuropore closure, which occurs by the end of week 4. Note that the cranial (anterior) neuropore closes by day 25 and the caudal (posterior) neuropore closes by day 28. The brain and most of the spinal cord (up to L1-L2) forms from the neural plate-derived neural tube through primary neurulation. The remaining caudal component of the spinal cord forms from local tissues through secondary neurulation.



Describe neuroepithelium formation of CNS neuroblasts and glioblasts in neural tube differentiation
to form the embryonic spinal cord’s mantle layer (with alar and basal plates) and marginal layer.

Neuropeithelium makes up the walls of the newly formed neural tube and surrounds the neural tube lumen/neural canal.
Neuroepithelial cells proliferate and differentiate into CNS neuroblasts, which are precursor/primitive neurons. (Neuropeithelium also forms neuroglial cells). The newly formed neuroblasts lose the ability to divide once they are formed and move outwards, from the inner
neuroepithelial layers that line the neural tube lumen. When neuroblasts migrate outside/superficial to the neuroepithelium, they are apolar and round. As the neuroblasts differentiate, they develop
cytoplasmic processes (axon/dendrites) and eventually become the adult nerve cells, or neurons. Neuroblast differentiation is a response to the environmental signals during migration and it is critical that developing neurons make appropriate connections so that they do not undergo apoptosis.
As neuroblasts develop, the *mantle layer forms outside of the neuroepithelial layer surrounding the neural tube lumen. The mantle layer is the future GRAY matter of the spinal cord, which contains
neuroblast/neuron cell bodies.
Superficial to the mantle layer, the marginal layer is the future white matter of the spinal cord, which contains myelinated axon processes that grow into it from neuroblast/ neuron cell bodies in the spinal cord gray matter, brain, and spinal ganglia. Thus, the developing spinal cord is made up of an innermost ventricular layer (with proliferating neuroepithelial cells), intermediate mantle layer (with migrated neuroblast cell bodies), and outermost marginal layer (with neuroblast axons). Note that the midline roof and floor plates are thinner and do not contain neuroblasts but contain nerve fibers crossing from one side to the other. As more and more neuroepithelium-derived neuroblasts are added, dorsal and ventral thickenings form in the mantle layer.
- The bilateral dorsal thickenings of neuroblasts make up the alar plates that form sensory areas known
as the dorsal horns. Neuroblast cell bodies in the alar plates (dorsal sensory horns) have axons that
penetrate into the marginal layer of the spinal cord, where they ascend to either higher or lower levels
as interneurons.
- The bilateral ventral thickenings of neuroblasts make up the basal plate that form motor areas known
as the ventral horns (nucleus of somatic motor neuron cell bodies) and lateral horns (nucleus of
autonomic presynaptic motor neuron cell bodies) in segments T1-L2.

Neuroblasts in the basal plates
(ventral motor horns) become multipolar somatic motor neuroblasts/neurons with cell bodies in nuclei
in the gray matter of the developing ventral horn and axons that break beyond the basal plate, through
the marginal zone, and through the ventral motor root of the spinal nerve to conduct impulses to
skeletal muscles. Realize that the neuron cell bodies in the basal plate are part of the CNS and their
outgrowing axons are part of the PNS


Identify initial development of the brain through neural tube differentiation into primary-secondary
vesicles and flexures.

As early as weeks 3-4 of prenatal development (even before closure of the neuropores), the brain begins to take shape as a result of cell proliferation at the rostral end of neural tube with formation of bulges/ dilations/bumps, known as brain vesicles, and bends, known as flexures.

The future spinal cord develops caudal to these dilated and bent regions. Initially, there are three primary brain vesicles: prosencephalon/forebrain, mesencephalon/midbrain, rhombencephalon/hindbrain. The caudal end of the rhombencephalon is continuous with the spinal cord.

With formation of the secondary brain vesicles, the pontine flexure is a bend that appears in the dorsal surface between the metencephalon and myelencephalon.

The 5 secondary brain vesicles continue growth to form the adult brain and brainstem and are detailed in upcoming sections.


Understand the spinal cord organization of sensory alar plates and motor basal plates in order to
compare/contrast arrangement in different parts of the brain.

Mesencephalon - basal plates are ventral, alar are dorsal to cerebral aqueduct of Sylvius. The alar plates form small crescents into the superior colliculi.
*the Edinger-Westphal nucleus - more dorsal basal plate that contains the parasympathetic to cranial nerve 3.

Rhombencephalon: sensory alar plates are lateral rather than dorsal to motor basal plates along the 4th ventricle.


Identify structures formed from the rhombencephalon/hindbrain, including the cerebellum, pons,
medulla and associations with CNs V, VI, VII, VIII, IX, X, XI, XII and the 4th ventricle.

The rhombencephalon divides into the metencephalon (forms pons and cerebellum; associated CNs V, VI, VII, VIII) and myelencephalon (forms medulla; associated with CN IX, X, XI, XII).
The pontine flexure does not persist as a bend in the future brainstem. The alar and basal plates in the rhombencephalon wall near the developing
pontine flexure spread apart along the rhombencephalon’s neural canal/lumen, known as the 4th

Thus, the basal plates and alar plates end up lying along the floor of the 4th
ventricle and the roof of the 4th ventricle is a thin membrane. In contrast to the dorsal sensory alar
plates and the ventral motor basal plates of the spinal cord, this region of the rhombencephalon (future pons and medulla) forms sensory nuclei that are located lateral (rather than dorsal/posterior) to motor nuclei.


Identify structures formed from the mesencephalon/midbrain, including the adult midbrain
structures and associations with CNs III, IV and the cerebral aqueduct of Sylvius.

.The mesencephalon is the midbrain (associated with CNs III, IV).

The mesencephalon is cranial to the spinal cord and rhombencephalon and forms the midbrain component of the brainstem. The mesencephalon contains basal and alar plates. The nuclei of the basal plates are made of two groups of efferent/motor neurons in the mesencephalon whose axons course in cranial nerves III, IV to supply almost all extrinsic skeletal muscles of the eye (for eyeball movement).

Neuron cell bodies that make up the Edinger-Westphal nucleus in the midbrain send axons fibers through CN III to the innervate pupillary sphincter/constrictor muscle and ciliary muscle

The dorsally-located alar components of the midbrain are colliculi that serve as sensory synaptic relays for visual and auditory information. The colliculi are formed by neuroblasts migrating to the overlying marginal zone.
The cerebral aqueduct (of Sylvius) forms from the lumen of the mesencephalon.


Identify structures formed from the prosencephalon/forebrain, including cerebral hemispheres,
thalamus, hypothalamus, optic vesicles, anterior pituitary, pineal gland and associations with CNs I, II
and the lateral-3rd ventricles.

Prosencephalon - divides into the telencephalon (forms cerebral hemispheres; associated with CN1) and diencephalon (forms optic cup, pineal gland, thalamus, hypothalamus posterior pituitary; associated with CN II)

- Optic vesicles evaginate from the diencephalon and are associated with CN II/optic nerve-tract-chiasma. Optic vesicles induce the overlying surface ectodermal lens placode to form the lens.
- The diencephalon consists of a roof plate, two alar plates, no (or very little) floor or basal plates.
The most caudal part of the roof
plate develops into the pineal body/epiphysis for light-darkness behavioral rhythms.
- The alar plates form the lateral walls of the diencephalon. Neuroblast in the alar plates of the
diencephalon walls proliferate to form `the hypothalamus and thalamus. The thalamus proliferates
and bulges into the lumen of the diencephalon. The hypothalamus differentiates into a number of
nuclear areas that regulate visceral functions, including sleep, digestion, body temperature, emotional

- The hypophysis/pituitary gland, develops form two completely different parts:

The posterior pituitary/neurophypophysis forms from the infundibulum, a ventral extension of the
• The anterior pituitary forms from the adenohypophyseal placode that buds off the primitive oral cavity immediately anterior to oropharyngeal membrane as Rathke's pouch. The developing anterior pituitary grows towards the infundibulum and loses its connection with the oral cavity

- Development of the brain is dominated by dramatic growth of bilateral outpocketings/projections/
evaginations/swellings of the telencephalon to form cerebral hemispheres. The cerebral
hemispheres grow to cover other brain regions (diencephalon, midbrain, hindbrain) and meet/flatten
medially in the midline.
Growth of the cerebral cortex (outer gray matter) forms lobes (frontal, parietal, temporal, occipital) and increases surface area through foldings that form sulci, fissures, gyri.
- In the cerebrum, the lamina terminalis is an early bridge between two cerebral hemispheres where
tracts (fiber bundles) interconnect the two cerebral hemispheres.
Continued tract formation for cross
communication between the cerebral hemispheres forms commissures. The anterior commissure
and corpus callosum (two prominent commissures in the adult brain) maintain attachments to the
lamina terminalis.
- The basal part of the telencephalon, adjacent to the diencephalon, thickens to form the gray masses
called the basal nuclei. The hippocampus and cranial nerve I (olfactory bulb and tract/nerve) are
also derived from the telencephalon.
- The neural canal/lumen of the telencephalon become the cavities of the hemispheres, the lateral
ventricles, which communicate with the lumen diencephalon through interventricular foramina of

- By birth, the cerebral cortex in the outer gray matter is made up of six layers that form as multiple
waves of neuroblast migration from the ventricular layer of proliferating neuroepithelial cells. Layer
formation occurs as each neuroblast wave migrates superficially to the subpial position and
differentiates into fully mature neurons. When the next wave of neuroblasts arrives, neuroblasts
migrate through the earlier formed layers of cells until they reach the subpial position. Thus, the early
formed neuroblasts are deep position in the cortex (layer VI), whereas those formed later obtain a
more superficial position (layer I).


Relate the neural tube lumen to the ventricular system, which produces and carries CSF.

The cavity/lumen of the neural tube persists as a system of ventricles.
The neural canal/lumen
- within the telencephalon region of the neural tube forms hollow cavities in the cerebral hemispheres
called lateral ventricles, which have openings called the interventricular foramina of Monro
- within the diencephalon forms the third ventricle
- within the midbrain forms the cerebral aqueduct (of Sylvius)
- within the rhombencephalon forms the fourth ventricle, which has median and lateral apertures
(foramina of Magendie and Luschka, respectively)
- within the spinal cord forms the central canal.


Explain development of neural crest cells and their migration and differentiation into PNS neuroblasts
and glioblasts. Describe the neuroepithelium, neural crest, ectodermal placodes

Neural crest cells (NCCs) detach from the dorsolateral edges of the fusing neural tube and migrate
throughout the body to form a wide variety of cell types. These migratory stem cells form
- nervous tissues cells of PNS (neurons in sensory and autonomic ganglia and neuroglial Schwann cells
and satellite cells)
- mesenchymal cells that differentiate into fibroblasts, adipocytes, chondrocytes, osteocytes,
odontoblasts to form tissues in the head-neck (connective tissue, cartilage, bone, dentin, arachnoid-
pia) and heart (valves/septa)
- melanocytes (epidermis, eye)
- some endocrine cells (thyroid C/parafollicular cells, parathyroid chief cells found in ultimobranchial
body of 4th pharyngeal pouch, adrenal medulla chromaffin cells)
Neural crest cells form the PNS’s
- sensory ganglia associated with spinal nerves to form all dorsal root ganglia - sensory ganglia associated with the proximal or superior ganglia portions of CN V, CN IX, CN X - autonomic motor ganglia, including sympathetic paravertebral and prevertebral ganglia,
parasympathetic intramural ganglia in the trunk associated with CN X, parasympathetic cranial ganglia in the head (ciliary, pterygopalatine, submandibular, otic) associated with CN III, CN VII, CN IX

Placodes are surface ectodermal thickenings in the embryonic head region that contribute to
development special sensory system components for smell, vision, taste, hearing.

- The nasal/olfactory placode forms the olfactory epithelium associated with CN I.
- The optic/lens placode forms the lens of the eye and develops adjacent to the diencephalon’s optic
- The otic placode forms the inner ear’s vestibulocochlear apparatus associated with CN VIII.
- The trigeminal placode and epibranchial placodes (3) form sensory ganglia associated with distal or inferior ganglia portions of CN 5,7,9,10.
- The adenohypophyseal placode forms the anterior pituitary gland.


What are neural tube defects

Neural Tube Defects (NTDs) are severe congenital defects (birth defects) of the CNS that usually result from failure of neuropores to close during week 4.
If neuropores remain open, abnormalities in skin,
skull, vertebrae, meninges, muscles, neural tissues may be seen and there is a connection between the amniotic cavity and vertebral canal.
- In 1/5000 live births, defective closure of the cranial neuropore results in anencephaly and the failure
to form the cranial vault around cerebral hemispheres. Anencephaly is lethal (usually) because the
malformed brain is exposed to amniotic fluid, which leads to its degeneration and necrosis. Because
anencephalic fetuses lack swallowing reflex, the last trimester of pregnancy is characterized by
polyhydramnios (excess amniotic fluid in sac) and is a risk factor is maternal type 1 diabetes.
- Defective closure of the caudal neuropore results in spina bifida, in which there is at least a defective
fusion of vertebral arches (commonly at L4-S1).
- Defective closure of the entire neural tube CNS is seen as an open furrow on the dorsal surface of the
head and body and results in a fatal deformity called craniorachischisis (“cleft skull and spine”).
Spina bifida occulta does not cause disability and is usually an incidental finding during back x-ray. It
is present in 10% of otherwise normal people as a defect in the fusion of vertebral arches (usually S1-S2) without herniation of underlying neural tissue and is covered by skin which may or may not grow an
abnormal tuft of hair in the region over the defect.

-Spina bifida cystica is a severe defect in the fusion of vertebral arches in which neural tissue and/or meninges protrude through the defect in the vertebral
arches and skin. It is a severe defect in the fusion of vertebral arches with involvement of underlying
neural tissue that appears as a cyst-like sac and results in neurological deficits (but not usually
associated with intellectual disability). Spina bifida cystica includes the following types:
- spina bifida cystica with meningocele in which only fluid-filled meninges protrude through defect
- spina bifida cystica with meningomyelocele in which fluid-filled meninges and neural tissue protrude
through defect; Hydrocephaly often develops in children with severe NTDs. For example, in some
infants with spina bifida with meningomylocele, there is also Arnold-Chiari malformation (type II) in
which the spinal cord is abnormally tethered to the growing and lengthening vertebral column that
pulls the cerebellum inferiorly to herniate into the foramen magnum and obstructs CSF flow. There
may also be paralysis and sensory loss at and below the level of the lesion. (Hydrocephalus can be
treated by inserting a ventriculoperitoneal shunt, which allows drainage of CSF from one of cerebral
ventricles into peritoneal cavity.)
- spina bifida cystica with rachischisis/myeloschisis in which neural folds do not elevate and fuse

Defects in skull formation, frequently in the occipital region, can also result in
- meningoceles in which only meninges bulge through a small opening in the skull
- meningoencephaloceles in which meninges and brain bulges through a large opening in the skull
- meningohydroencephaloceles in which meninges, brain tissue, and ventricles bulge through a larger
opening in the skull


How are severe NTDs screened?

Detecting AFP levels:
Alpha-fetoprotein (AFP) is an abundant plasma protein of fetal serum that is produced by fetal yolk sac and liver. AFP passes through fetal urine into amniotic fluid and reaches maternal blood. AFP can also directly pass into amniotic fluid if there is a NTD (or abdominal wall defect) and result in elevated AFP
levels in amniotic fluid and maternal blood. Screening for severe NTDs that involve herniation of neural tissues is accomplished by measuring for elevated AFP levels in maternal blood at 15-20 weeks gestation.

Acetylcholinesterase (AChE) is primarily active in the CNS and normal amniotic fluid does not contain AChE, unless contributed by the fetus as a result of an open NTD. Elevated AFP and acetylcholinesterase are indicators for fetal ultrasonography. The most common cause of elevated AFP levels is underestimation of gestational age/dating error. Prenatal ultrasound is used to confirm
gestational age and for detection/diagnosis of NTDs or abdominal wall defects. Surgery can be
performed in utero at ~22 weeks to repair the defect.


Describe neuroepithelium formation of CNS glioblasts

After production of neuroblasts ceases, the neuroepithelium forms CNS glioblasts that differentiate into most neuroglia of the CNS (except macrophage-derived microglia).

Glioblasts migrate to mantle and marginal layers.
- In the mantle layer, glioblasts differentiate into astrocytes.
- In the marginal layer, glioblasts differentiate into oligodendrocytes that form myelin sheaths around
axons. Oligodendrocyte myelination of axons within the CNS is essential for efficient and rapid
transmission of signals. Myelination begins in the spinal cord at ~4th month of gestation and is not
completed until after the first year of birth. Myelination in the brain begins at ~6th month of gestation
and much remains unmyelinated at birth, with myelination not complete for many years (even
decades) after birth.
- When neuroepithelial cells cease to produce neuroblasts or glioblasts, they differentiate into
ependymal cells, as seen lining the central canal in the spinal cord.
- Note that microglial cells are macrophage-derived phagocytic cells in the CNS (yolk sac origin).


origins of cranial
nerves and ganglia.

The 12 pairs of cranial nerves are made up of a mixture of neurons with different functions and different origins.
Cranial nerves I and II emerge from the forebrain, cranial nerves III and IV emerge from the
midbrain, cranial nerves V, VI, VII, VIII, IX, X, XI, XII emerge from the hindbrain.
rise to the CNS’s GSE, GVE, SVE motor nuclei in the
brainstem with axons coursing through cranial nerves. Neuropeithelium in the midbrain forms motor
nuclei associated with axons that course through CN III to supply skeletal-smooth muscles in the eye.
Neuroepithelium in the hindbrain forms motor nuclei associated with CN IV, CN V, CN VI, CN VII, CN
IX, CN X, CN XI, CN XII to supply skeletal-cardiac-smooth muscles and glands in the head, neck,
trunk regions. (Note that although CN IV nuclei originate in the rhombencephalon, they migrate into
the mesencephalon and the trochlear nerve emerges from the midbrain.)


What is contained in the diencephalon/what does it give rise to?

The diencephalon gives rise to optic vesicles > (retina, optic nerve)

Epiphysis - pineal gland

Pituitary (posterior lobe) - from the infundibulum (ventral extension of the diencephalon) and combine with Rathke's pouch which is coming from the oral cavity

Thalamus and hypothalamus

Surrounds the 3rd ventricle.


What is Rathke's pouch

In embryogenesis, Rathke's pouch is an evagination at the roof of the developing mouth in front of the buccopharyngeal membrane. It gives rise to the anterior pituitary (adenohypophysis), a part of the endocrine system.