Chapter 4 - Development

The brain begins as an infolding of ectoderm on the dorsal aspect of the embryo around 18 days from conception (figure 7). The ectoderm has a default program to develop the neural tube but produces a protein, bone morphogenic protein (BMP) that blocks development of neural tube. This is one of the "transforming growth factor beta" (TGF-beta) family of proteins. The notocord secretes several factors (noggin, chordin and folistatin) that inhibit BMP, triggering formation of the neural epithelium over the notocord. This produces a dorsal longitudinal fold, the "neural groove," that begins closing into a tube in the cervical area at around day 20. It "zips up" rostrally and caudally to complete the tube around 28 days. The hollow of the tube becomes the ventricular system and the walls become the brain and spinal cord.

Cellular proliferation and migration

The cells comprising the walls of the neural tube undergo massive proliferation. Some of these cells become neural precursors (neuroblasts) and some become glial precursors (glioblasts) under the influence of proteins called "notch" and "delta" which are expressed on these cells. This prevents all cells from developing into neurons or all into glia.

Cells proliferate in the region of the tube adjacent to the cavity (the ventricular zone). There are long, thin glia (radial glia) that maintain contact between the inner and outer edges of the wall of the tube. There are contact factors on the surface of the radial glia and on the developing neurons that guide radial migration of cells from the ventriclular zone of the tube into the mantle zone of the neural tube, a layer that adds to the outside of the neural tube. This mantle zone becomes most of the substance of the spinal cord and brain. As axons begin to move out from the cells, they enter the periphery of the tube, comprising the marginal zone. The spinal cord maintains this general organization into adulthood, with the ependymal cells being the only remnant of the ventricular zone, the gray matter representing the mantle zone and the white matter the marginal zone.

Migration is a little more complex in the rostral part of the brain, the portion that becomes the cerebral cortex. Radial glia maintain connections to the very surface of the cerebral cortex for a long time (this surface layer becomes cortical layer I). Then there are 5 waves of neuronal migrations into the cerebral cortex (representing cortical layers II-VI). Each wave migrates though the prior set of neurons until they bump up against cortical layer I. This means that the oldest layer of the cortex is layer I, but the next oldest (developmentally) is layer VI. Migration continues for quite some time and is subject to being disrupted.

Brain vessicles

The head end of the neural tube folds ventrally at the cervical flexure and cephalic (mesencephalic) flexure and then expands into primary brain vesicles. These primary vesicles are, from caudal to rostral, the rhombencephalic, mesencephalic and prosencephalic vesicles. The primary vesicles become secondary vesicles. A dorsal fold develops in the rhombencephalon (pontine flexure) that divides the rhombencephalic vesicle into the myencephalic vesicle (the myelencephalon becomes the caudal part of the 4th ventricle, i.e., the medulla) and the metencephalic vesicle (the metencephalon becomes the rostral part of the 4th ventricle, i.e., the pons). Rostrally the prosencephalic vesicle develops a midline vesicle (the diencephalic vesicle, that becomes the third ventricle) and lateral outpouchings (that become the telencephalic vesicles, which develop into the lateral ventricles).

Neural tube structure

The neural tube has a ventral portion (the basal plate) and a dorsal portion (the alar plate). The main signal that triggers the development of the ventral part of the neural tube is a gene product called "sonic hedgehog" (shh), which is produced by the notocord and the floorplate of the neural tube. Absence of sonic hedgehog will result in holoprosencephaly. There are other signals that are responsible for the development of the dorsal aspect of the neural tube. These derive from overlying skin and include many of the TGF-beta family (including BMP, vitamin A and dorsalin). Ventral-dorsal gradients of these various molecules pattern the development of the spinal cord and brain stem.

The basal plate in the spinal cord and brain stem is destined to contain most of the motor neurons while the alar plate contains sensory neurons. Additionally, cells in the developing cervical region accumulate retinoic acid that diffuses rostally into the developing head. The expression of a Hox genes is dependent on the specific concentration of retinoic acid to which a developing neuron is exposed. The set of Hox genes expressed will determine the rostral-caudal organization of the brain stem from the developing neural tube. This is why vitamin A (or lack of this vitamin) or administration of analogues of vitamin A can be so teratogenic.

Throughout the brain stem, the general organization of the spinal cord is maintained with the exception of the development of the fourth ventricles that displace the alar plates dorsolaterally (figure 8). Nonetheless, the cranial nerve nuclei that are ventral and medial (in the basal plate) are motor and those that are dorsal and lateral are sensory. There is a shallow groove on the floor of the fourth ventricle (the sulcus limitans) that defines the separation between alar and basal plates and cranial nerve nuclei located near this sulcus are associated with visceral functions.

The retina develops directly from the neural tube as an outpouching from the diencephalic vesicle while inner ear formation is induced in the overlying ectoderm by the presence of the rhombencephalon.

The cerebellum undergoes very late development from the dorsal lips of the metencephalon ("rhombic lips"). This region continues to develop even postpartum. The frontal lobes of the cerebral cortex are also rather late to develop, particularly in terms of myelination of the white matter connections.

Neural crest

Much of the peripheral nervous system develops from neural crest cells (figure 7). All of the sensory neurons and postganglionic sympathetic neurons develop from these cells as do the supporting cells of the in the ganglia and the Schwann cells. Neural crest cells also become all of the chromafin cells, the melanocytes and, in addition, contribute to development of the outer layers of the eye and many of the skull bones.

Chemical signalling

It appears that the ultimate fate of the developing neurons depend on several factors. First of all, neurons respond to the environment through which they migrate, changing their character depending on environmental signals. Additionally, it is critical that neurons make appropriate connections since, if they do not, they undergo apoptosis (a non-inflammatory, non-necrotic form of cell death). This appears to be dependent on appropriate and complex trophic interaction between neurons and targets.

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