Development of the Nervous System

• Humans have around 10^11 neurons.
• These neurons are wired predictably and arranged similarly in brains.
• Chemical signals induce stem cells to differentiate into parts of the nervous system.
• The CNS develops from a simple tube, understanding this aids in comprehending the arrangement of the brain and malformations.

Notochord and Neural Plate

• At the end of the first week, cells for tissues and organs reside in an epithelial disk (epiblast).
• Gastrulation during the second week establishes the three tissue layers: ectoderm, mesoderm, and endoderm
• It also creates the midline and rostral-caudal axis.
• Around day 8, a band of rapidly dividing cells forms the primitive streak
• It's arranged like a radius across the epiblast, ending in the primitive node.
• Newborn cells dive through the epiblast at the primitive streak and node.
• They spread to form mesodermal and endodermal layers.
• Epiblast cells staying behind become the ectoderm, for skin and the nervous system.
• Cells moving through the primitive node form a mesodermal rod, the notochord, extending from the primitive streak.
• The primitive streak and notochord define the embryo's midline.
• Notochord remnants persist post-birth as the nucleus pulposus within intervertebral disks.
• The notochord marks the rostral-caudal axis of the CNS.
• Its origin near the primitive node underlies the lumbar spinal cord.
• The notochord ends near the future diencephalon.
• The notochord secretes signaling molecules like sonic hedgehog.
• This signals the overlying midline ectoderm to thicken into the neural plate.
• As the notochord induces the neural plate, the ectoderm and nearby tissues release their signaling molecules.
• Opposing gradients from these molecules change differentiation and growth.
• Cells near the midline become motor neurons.
• Cells in more lateral parts of the neural plate become sensory neurons.
• Cells at the junction of the neural plate and ectoderm become neural crest cells.

Neural Tube Formation

• During the third week, a longitudinal groove (neural groove) appears in the neural plate, flanked by a neural fold on either side.
• Neural crest cells grow at the apex of each neural fold.
• The neural folds enlarge and meet in the midline at the level of the future cervical spinal cord, forming the beginning of the neural tube.
• Additional closure sites appear and zip up in rostral and caudal directions.
• As closure progresses, neural crest cells separate from the neural folds and form a layer over the neural tube, between it and the surface ectoderm.
• The neural tube closes up and detaches from the surface ectoderm by the end of the fourth week.
• Neurulation, the formation of the neural tube, is a major developmental event
• The neural tube will become the entire CNS
• Its cavity becomes the ventricular system of the brain.
• The sacral spinal cord forms after neural tube closure through secondary neurulation
• The neural tube extends into a stem cell mass at the caudal end of the spinal cord.
• Neural crest cells migrate to form the neurons and glial cells of the peripheral nervous system
• They also form cutaneous melanocytes, the adrenal medulla, and nonneural tissues in the head.
• This includes primary sensory neurons of spinal and cranial nerve ganglia.
• It also includes autonomic neurons and Schwann and satellite cells of peripheral nerves and ganglia.
• Placodes of neural crest-like cells initially in the surface ectoderm detach later and form the remainder of the PNS in the head.

Defective Neurulation

• Defective neurulation is relatively common, affecting approximately 0.1% of infants.
• It effects even higher percentages of fetuses that do not survive to term.
• Neural tube defects lead to different abnormalities in the CNS.
• Neural tube defects also lead to abnormalities in the skull and vertebrae.
• Craniorachischisis is a fatal condition where the neural tube does not close, and neural tissue is continuous with the skin.
• Anencephaly results if only the rostral end of the neural tube fails to close.
• In this case, the skull is absent and most of the cerebrum is replaced by exposed neural tissue.
• The face and the rest of the skull develop because of the notochord and ventral neural tube.
• Spina bifida occurs if the caudal end of the neural tube fails to close
• This ranges from spinal cord exposure to vertebral arch deficiencies with herniation of spinal cord or meninges.
• Milder forms may be asymptomatic with a single defective vertebra, indicated by a tuft of hair or dimple.
• Hirschsprung's disease is due to a proliferation or migration defect of neural crest cells, with defective innervation of a colon segment.
• The affected segment constricts, restricting passage of intestinal contents, causing proximal dilation (congenital megacolon).

Clinical Note: Detecting Neural Tube Defects

• Alpha-fetoprotein (AFP) is synthesized in the fetal liver and is a major component of fetal serum.
• Some is normally excreted into amniotic fluid through fetal urine.
• In open neural tube defects, more than the normal amount of AFP leaks into cerebrospinal fluid, amniotic fluid, and maternal serum.
• Measuring AFP levels during gestation is a useful screening test for neural tube defects.

Biochemistry Note: Preventing Neural Tube Defects

• Adequate folic acid is essential for rapidly dividing cells because of its role in DNA synthesis.
• Folic acid supplementation may prevent more than 50% of neural tube defects.
• Because neurulation occurs early, supplementation must be provided near the time of conception.
• Folate is added to parts of the food supply in some countries for this reason.

Brain Vesicles

• The neural tube is not straight.
• Even before closing, the brain part of the tube develops curves and creases, laying the groundwork for the arrangement of its future parts.
• During the fourth week, three primary vesicles appear: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain).
• The prosencephalon becomes the cerebrum.
• The mesencephalon forms the midbrain.
• The rhombencephalon forms the pons, medulla, and cerebellum.
• Less than a week later, bulges grow on each side of the prosencephalon, and differences appear in the rostral and caudal halves of the rhombencephalon.
• The prosencephalon gives rise to the telencephalon and diencephalon.
• The rhombencephalon gives rise to the metencephalon and myelencephalon.
• The mesencephalon remains undivided.
• Each telencephalic vesicle develops into a cerebral hemisphere.
• The diencephalon becomes the thalamus, hypothalamus, and other structures.
• The metencephalon becomes the pons and cerebellum.
• The myelencephalon becomes the medulla.
• The neural tube cavity persists as a system of ventricles.

Flexures in the Neural Tube

• There are three prominent bends that appear when embryonic vesicles are forming.
• The midbrain bends around the rostral end of the notochord, forming the cephalic flexure.
• The cephalic flexure persists as the bend in the CNS between the brainstem and cerebrum.
• The cervical flexure appears between the spinal cord and brainstem and straightens out later.
• The brainstem bends anteriorly in the pontine flexure.
• The pontine flexure does not cause a long-term bend but determines the shape of the fourth ventricle and the position of the cerebellum.

"Rotation” of the Cerebral Hemispheres

• After embryonic vesicles form, massive growth of the telencephalon dominates remaining CNS development.
• Each telencephalic vesicle expands in all directions from the diencephalon.
• The medial and inferior vesicle parts fold down and fuse with the diencephalon where the basal ganglia will form.
• This fusion develops a cortical covering and sets a fixed pivot point as the hemisphere expands.
• The insula is overgrown by parts of the frontal, parietal, and temporal lobes.
• Structures like the lateral ventricle and the caudate nucleus are dragged into a C shape.

Malformation of the Prosencephalon

• The prosencephalon subdivides early.
• Problems with this subdivision cause holoprosencephaly.
• In severe forms, olfactory bulbs, tracts, and the optic chiasm are missing.
• Cerebral hemispheres are undivided, and the corpus callosum is absent.
• There is a single ventricle that spans the midline.
• Effects on the skull and face are opposite to those in anencephaly
• The development on in holoprosencephaly dorsal and posterior skull is present.

Proliferation, Migration, and Differentiation of Neurons

• Neural tube closure and prosencephalon formation occur in the first month of development.
• This is followed by massive proliferation of neurons and glial cells during the third and fourth months and later.
• Cells than migrate to their final locations and differentiate into specific cell types.

Neurogenesis

• The simple neural tube has a pseudostratified columnar epithelium, a single cell thick.
• Early on, each cell spans the entire epithelium, its nucleus shuttling between the ventricular and external surfaces.
• As the nucleus moves outward, its DNA replicates.
• As it moves inward, the cell retracts its surface-directed process and divides.
• The two daughter cells either repeat the process, or one or both leave the mitotic cycle, commit to being a progenitor cell, and migrate to a final destination.
• The final round of mitosis happens before birth in almost all CNS areas
• The last cells left near the lumen of the neural tube transform into the ependymal cells.
• Neural progenitors accumulate outside the mitotic area, dividing the neural tube wall into three zones: ventricular, intermediate, and marginal.
• The ventricular zone contains stem cell nuclei that shuttle and divide.
• The intermediate zone contains committed precursor cells.
• The marginal zone is relatively cell-free with surface-directed processes of stem cells.
• In the spinal cord, the ventricular zone becomes the ependymal cells surrounding the central canal.
• The intermediate zone becomes the spinal gray matter.
• The marginal zone becomes the white matter, invaded by ascending and descending tracts.
• The sequence is complex in other CNS regions.
• In the telencephalon, for example, some neurons stay close to the lateral ventricles, forming the basal ganglia and amygdala.
• Other neurons migrate longer distances to form the cerebral cortex, with newborn neurons migrating past existing cortical neurons, forming the cortex from the inside out.

Abnormalities of Proliferation and Migration

• Neural stem cell divisions, timing of divisions, and migration of newborn neurons need control for proper CNS wiring.
• Micrencephaly ("small brain") results if too few cell divisions occur or too few stem cells are formed.
• If neuron migration to the cortex is abnormal, gyri do not form properly.
• Lissencephaly ("smooth brain") occurs when a large percentage of neurons stop before reaching the cortex.
• As a result, the surface area of the cortex is reduced, and gyri do not form.
• Heterotopic clumps of gray matter result if neurons get "stuck" in the white matter before reaching the cortex.

Longitudinal Zones in the Central Nervous System

• Signaling molecules induce the roof and floor plate from the nearest neural tube parts.
• The signaling molecules are the same and are released by the surface ectoderm and notochord
• The roof and floor plates thin out and the lateral walls develop into various parts of the CNS
• Seen most clearly in the spinal cord where alar and basal plate near roof and floor plate respectively.
• Alar and basal plate are separated by the sulcus limitans, running longitudinally
• Alar and basal plate form posterior and anterior horns containing sensory and motor neurons
• Preganglionic autonomic neurons are at intermediate gray matter near where the sulcus limitans used to be.
• The cavity becomes the central canal, where little tissue is left.
• The organization continues into the rhombencephalon which spreads the neural tube walls and stretches the roof plate out.
• The elongated roof plate becomes the top of the fourth ventricle.
• The alar and basal plates form the floor of 4th ventricle with alar plate lateral
• This extends development into sensory and motor functions.