Stages and timing of development of the nervous system.
Note that there is partial temporal overlap of the different
Developmental Organization of the
Nervous System:
Neuroembryology
• Neural development is controlled by soluble signals
from the mesoderm, target-derived growth factors,
and adhesion molecules
• These substances control the expression of
transcription factors that regulate genes involved in
determining neuronal or glial fates
• These substances also control the dynamics of
cytoskeletal proteins required for axonal & dendritic
growth
Formation of Neural Tube
• The CNS of vertebrates arises from the dorsal
midline ectoderm of the vertebrate gastrula
• Neural Induction - transformation of these
ectodermal cells into neural cells
- results in the formation of the neural
plate
Overview
• Provides framework and background for understanding
the anatomy of the nervous system in the adult
• Serves as an aid in understanding the pathogenesis of
developmental neurologic abnormalities that are
encountered not only in the newborn and pediatric
periods but also in later life
Signals involved in the development of the nervous system.
• The neural tube is formed in 7 to 10 days, beginning
on the 18th day of gestation
• Primary neurulation - formation of the neural tube
as far caudally as the future S2 level
• Secondary neurulation - process whereby cavity of
neural tube extends into the caudal eminence
- gives rise to lower sacral cord, conus
medullaris, & filum terminale
processes.
Formation of the neural plate and neural tube
Neural Plate
Neural Fold
Closure of Neural
Tube
• Neural induction involves the activity of an
organizer, Hensen node
• Anterior visceral endoderm - underlies the future
neural plate, is required for induction of the
formation of the forebrain
• Induction and patterning of NS occur in several
steps
- during a first step, the anterior visceral endoderm and
precursors of the node elicit early neural induction
and specify the forebrain
- during a final step called caudalization, or
posteriorization,signals from the node specify the
midbrain, hindbrain, orspinal cord
• 18th day of gestation
- formation of neural tube begins
- early stage of gastrulation is completed
- 2-layered embryo consisting of ectoderm &
endoderm is transformed into a 3-layered
structure by the outgrowth of mesoderm from
the midline primitive streak

• Notochord
- grows forward from the anterior end of the
primitive streak (Hensen’s node)

• Neural Groove
- lateral edges of
Neural Crest
neural plate thicken - cell columns
Neural Plate more rapidly than - derived from the
the center, begin to junction of skin
- formed from
roll toward the
induction of the ectoderm &
midline neuroectoderm
ectoderm overlying
the notochord • Neural Folds
separate from the
• Neural Tube neural tube & form a
- closes first in the major portion of the
middle of the
PNS
embryo
• Neuropores

• Primary brain vesicles: Subdivisions of the primitive Nervous System

- prosencephalon, mesencephalon, rhombencephalon
- further differentiate into 5 subdivisions

Somites
- aggregation of
mesodermal cells
- bone & muscle arise

• Spinal cord
- formed from the remaining caudal end of the neural tube
• The subdivisions of the neural tube are the
precursors of 3 of the 4 major anatomical levels in
the adult:
1. supratentorial (telencephalon, diencephalon)
2. posterior fossa (mesencephalon, metencephalon,
myelencephalon)
3. spinal (spinal cord)
4. peripheral level consists of a combination of
efferent fibers that grow out from the posterior
fossa & spinal levels & neural crest derivatives that
include somatic and visceral afferent neurons &
postganglionic autonomic neurons
Cell Proliferation, Differentiation, Migration, and
Maturation
• Through 4 processes that occur in concert, the cells
that make up the mature nervous system:
1. accumulate in sufficient number
2. develop into the appropriate type of cells
3. move to specific sites
4. make specific connections with other cells
• The primitive neural tube consists of
ventricular, subventricular, and marginal
zones:
3. Subventricular Zone
- adjacent to the lateral ventricles may
support neurogenesis in the adult brain
Major Stages of Development and the Corresponding
Developmental Disorders
Cell Proliferation
• The wall of the primitive neural tube initially
consists of a single layer of neuroepithelial cells that
are derived from the ectoderm and form a
pseudostratified epithelium
• These cells have an apical-basal polarity, with the
apical portion in contact with the central cavity and
the basal portion in contact with the outer surface
of the tube
• Developmental Cell Death:
- many neuronal and glial precursors created
during the proliferative phase are removed
through programmed cell death, or apoptosis
- the main stimulus for programmed cell death
during development is deprivation of growth
factors
• The neuroectodermal derivatives of the neural tube
& neural crest give rise to the sensory, motor,
internal regulation, and consciousness systems
• Mesodermal tissues surround the neural tube and
form the meninges, which in conjunction with the
ventricular system form the cerebrospinal fluid
system
• Mesoderm that surrounds and grows into the neural
tube forms the vascular system
• The primitive neural tube consists of ventricular,
subventricular, and marginal zones
1. Ventricular Zone
- primary germinative zone and contains pluripotent
neuroepithelial stem cells
- neuroepithelial cells of the ventricular zone are stem
cells that give rise to progenitors of neurons and glial
cells that accumulate in the subventricular zone
2. Marginal Zone
- consists of the radially extended cytoplasmic
processes of cells of the ventricular and subventricular
zones
- radial glia, derived from neuroepithelial cells, may
generate neurons during embryogenesis and then
differentiate into mature astrocytes
Differentiation of the cell layers in the primitive neural
tube

Differentiation of the Neural Tube
A. Longitudinal differentiation
- formation of forebrain, midbrain, hindbrain, and
brachial arches and placodes with closure of
neuropores
B. Transverse differentiation of neural tube
- formation of alar plates (dorsolateral) and basal
plates (ventrolateral) separated by sulcus limitans
Transverse differentiation
• As the neural tube enlarges and rostrocaudal
patterning occurs, the neural tube undergoes
anatomic and functional differentiation in the
transverse plane
• In a transverse section, the region of the neural tube
nearest the thoracic and abdominal cavities is
described as ventral and the region farthest from
them, as dorsal
Longitudinal differentiation
• Even before the neural tube is entirely closed,
longitudinal differentiation begins
• The cephalic, or head, end of the neural tube
becomes larger than the caudal end, producing an
irregularly shaped tubal structure
• Continued differential growth along the length of
the neural tube results in the formation of three
cavities at the cephalic end of the tube
• The central cavity of the neural tube remains as the
ventricular system
Derivatives of the Neural Tube and Neural Crest
Transverse differentiation
• The differential proliferation of cells in the dorsal
and ventral regions on each side results in the
formation of a longitudinal groove, the sulcus
limitans
• The sulcus limitans divides the neural tube into a
dorsal region, or alar plate, and a ventral region, or
basal plate
Longitudinal differentiation
1. Prosencephalon
- forms telencephalon and diencephalon
- Telencephalon:
dorsal zone - cerebral cortex
ventral zone - basal ganglia
- Diencephalon:
thalamus, hypothalamus, optic nerves, & pineal
gland
2. Mesencephalon - forms the midbrain
3. Rhombencephalon
- forms metencephalon and myelencephalon
- Metencephalon - pons & granule cells of cerebellum
- Myelencephalon - medulla
Transverse differentiation
• Alar plates give rise to afferent sensory structures in the
brainstem and spinal cord, including dorsal horns
- neurons receive peripheral sensory information from
derivatives of the somites (i.e., skin,muscle, joints, and
bone) or the endoderm (i.e., internal organs) and relay
this information to higher levels of the CNS
• AFFERENT is used to describe nerve fibers that conduct
information from the periphery toward the CNS
• These neurons & pathways constitute the SENSORY
SYSTEM
 Transverse differentiation
• The growth of the alar plate of the prosencephalon
results in large cerebral hemispheres,which almost
completely surround the derivatives of the
diencephalon
• The cerebral cortex, basal ganglia, and thalamus are
all derived from the alar plate
• The cerebellum arises from the proliferation of cells
of the alar plate, called the rhombic lip, in the
metencephalon and eventually covers the dorsal
surface of the entire rhombencephalon
Transverse differentiation
• • As a consequence of transverse differentiation,
the neural tube has a dorsal region, the alar plate,
and a ventral region, the basal plate
• Alar plate
- gives rise to all sensory neurons, cerebellum, and
cerebral hemispheres
• Basal plate
- gives rise to motor neurons & hypothalamus
• Cavity of the neural tube forms the central canal at
the spinal cord level and more complex fluid-filled
spaces, the ventricular system, at cephalic levels
Neural Tube Defects
• Multifactorial disorders
• Risk factors: family history, maternal risk factors
(obesity, diabetes mellitus, hyperthermia, use of
anticonvulsants, folate deficiency)
• Detected by increased levels of α-fetoprotein (AFP)
in maternal serum
• If serum AFP is increased, ultrasonography is
performed and amniotic fluid checked for AFP
Transverse differentiation
• The basal plate gives rise to the motor neurons of
the BS and spinal cord
• These neurons are EFFERENT - they conduct
impulses away from the CNS
• Motor neurons and pathways concerned with the
control of striated skeletal muscle constitute the
somatic motor system
• Those concerned with the control of internal organs
form the visceral motor system
• The basal plate of the diencephalon gives rise to the Transverse differentiation of the Neural Tube
hypothalamus, posterior pituitary, & optic nerve
• Primitive neuroectodermal cells proliferate &
differentiate into neurons, astrocytes,
• Cell columns called the neural crest separate from
oligodendrocytes, & ependymal cells
the neural tube and form a major portion of the
• Neuronal precursors (neuroblasts) migrate to their
peripheral nervous system
genetically coded location, guided by adhesion
• Cells of the neural crest differentiate into DRG,
molecules & glial cells
autonomic ganglia, & Schwann cells (peripheral glia)
• Axons grow toward their targets and establish
• Cranial nerves are derived from both the neural
specific synaptic connections with the appropriate
crest & specialized regions of ectoderm called
neurons
placodes
• These connections are stabilized by the activity of
the synapse and the presence of target-derived
factors
Types of Neural Tube Defects
A. Craniorachischisis
- congenital malformations of CNS due to defective D. Spina bifida occulta
neural tube closure during 1st trimester of pregnancy - defect in 1 or more vertebral arches
producing contiguous exposure of brain & spinal - spinal cord & meninges are normal
column
E. Cranium bifidum
B. Anencephaly
- absence of a major portion of the brain, skull, and
- defective fusion of cranial bones --> occipital
scalp portion of the cranium
- due to failure of anterior neuropore closure; defective - associated with herniated cerebral tissue and
notochord induction of the neuroectoderm meninges
C. Meningomyelocele (spina bifida cystica)
- herniatio
 F. Encephalocele Anencephaly Meningomyelocele
- extension of intracranial structures through
the cranial vault from a defect in fusion of
cranial bones
Meningocele - herniated meninges through skull
defect
Meningoencephalocele - herniated brain tissue
and meninges through skull defect
Meningohydrocephalocele - herniated brain
tissue, meninges, and ventricles through skull
defect

Spina Bifida
Myelomeningocele (spina bifida cystica)
- is herniation of the spinal cord and meninges
through a congenital defect in the vertebral arch. It
is covered with skin.

Cervical spina bifida, associated with Chiari type I

malformation. This needs to be differentiated from
Chiari type III malformation, which is essentially
herniated cerebellar and brainstem tissue.

Examples of failure of fusion at the spinal level.

Neuronal Migration Radial Migration

• Cranium bifidum. Defective fusion of the
cranial bones, most commonly in the occipital
part of the cranium. In this example, note
herniation of the meninges with cerebrospinal
fluid only (meningocele).
• Occipital Encephalocele
• Frontal Encephalocele
• In the developing nervous system, neurons migrate
from their site of origin in the germinal centers to
their final destination,where they mature and
develop functional connections
• Neuronal migration requires dynamic changes in the
neuronal cytoskeleton
• It is guided by interactions between neurons and
the microenvironment, including glial cells and the
extracellular matrix
• These interactions are mediated by several adhesion
and guidance molecules
• Radial migration is critical for the formation of
laminated structures such as the cerebral cortex
• Radial migration follows the radial organization of
the germinative zones in the neural tube and
involves the radial glia,which provides a scaffold for
the directed migration of postmitotic neurons in the
brain
Radial migration is critical for the formation of the cerebral &
cerebellar cortices. Formation of the cerebral cortex involves
Tangential Migration
migration of precursors of pyramidal cells from the ventricular
• Tangential migration of neural precursors from the
zone to the periphery, toward the pial surface.
subventricular zone of the rostral forebrain is
important for development of the olfactory bulb
• Tangential migration is also involved in the
formation of the external granular cell layer of the
cerebellum
• This is a secondary germinal matrix that originates
at the end of gestation and is the source of granule
cells in the cerebellum
Neuronal Maturation
• After a neuron has reached its final location in the
CNS, it establishes appropriate contacts with other
neurons, both locally and at a distance - by
extending processes called NEURITES
• Most neurites become dendrites,which receive
information coming from other nerve cells
• The contact between the axon of a neuron and the
dendrites of the neuronal target is called a SYNAPSE
• Synapses are the basis for transmission of
information in the NS

Progressive neuronal differentiation involves

extension of dendrites and axons and formation of Neuronal Maturation
synaptic contacts.
• Maturation of the nervous system involves
mechanisms of axonal growth, dendritic
development, and synaptogenesis
• These are dynamic processes that persist
throughout life and are critical for
mechanisms of learning and repair in the
nervous system