Nervous System Development Proteins

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 Nervous System Development Proteins Background

The entire nervous system is of ectodermal origin. The progenitor cells for all the neurons and glial cells of the central nervous system begin as a further differentiation of ectoderm cells into a layer known as the neural groove. Neural groove formation is induced by chemical signals from the mesoderm. By the elevation and ultimate fusion of the neural folds, the groove is converted into the neural tube. Before the neural groove is closed to form the neural tube a ridge of ectodermal cells, the ganglion ridge or neural crest appears along the prominent margin of each neural fold. When the folds meet in the middle line the two ganglion ridges fuse and form a wedge-shaped area along the line of closure of the tube. The neural crest cells give rise to the peripheral nervous system (PNS) and other non-nervous tissues, whereas the neural tube becomes the central nervous system. Cells in both structures differentiate into glial cells of various types as well as into immature neurons that migrate, grow axons and dendrites, form synapses and mature.


Development of peripheral nerves

Neuronal differentiation in the PNS is segmental, determined by somite level. The neural crest cells are pluripotent cells that proliferate rapidly opposite the primitive segments and then migrate in a lateral and ventral direction to the sides of the neural tube, where they ultimately form a series of oval-shaped masses, the future spinal ganglia. These ganglia are arranged symmetrically on the two sides of the neural tube and, except in the region of the tail, are equal in number to the primitive segments. The cells of the ganglia are of two kinds, viz., spongioblasts and neuroblasts. The spongioblasts develop into the neuroglial cells of the ganglia. The neuroblasts are at first round or oval in shape, but soon assume the form of spindles the extremities of which gradually elongate into central and peripheral processes. The central processes grow medially and, becoming connected with the neural tube, constitute the fibers of the dorsal nerve roots, while the peripheral processes grow laterally to mingle with the fibers of the ventral root in the spinal nerve. The ventral and the dorsal nerve roots join immediately beyond the spinal ganglion to form the spinal nerve, which then divides into anterior, posterior, and visceral divisions.


Schwann cell development

Neural crest cells destined to become Schwann cells have to undergo 3 main developmental transitions. These are the formation of Schwann cell precursors (first found in mouse nerves at E12 and E13). The formation of immature Schwann cells (first found in mouse at E15) and, lastly, the postnatal and reversible generation of non-myelinating and myelinating mature Schwann cells (P0- P30 in mouse). The developing Schwann cells first encounter growing axons in the anterior parts of the somites where they are channeled to at the same time in development. Schwann cells migrate out proximodistally along the growing nerve fibers. The establishment of axonal contact triggers Schwann cell proliferation that continues for as long as the axon grows. The axons are gradually segregated as the Schwann cells proliferate, sending out their processes deeper into the nerve bundle to invest smaller bundles of axons. Eventually a one to one relationship is established between each Schwann cell and an isolated axonal segment to be myelinated. During this time, the Schwann cell also undergoes a substantial lateral elongation along the axon and secretes a basal lamina.


Axon-Glial crosstalk

Schwann cells and axons have an intimate relationship and a powerful mutual dependence mediated by various signaling molecules. This bidirectional communication at the axon-glial interface provides a way by which neurons and Schwann cells can support their mutual survival and differentiation during development and during the process of nerve repair after injury. Broadly speaking, neurons exert three classes of action on Schwann cells: 1) inducing or repressing proliferation; 2) stimulating differentiation; and 3) modifying migration/growth. Schwann cells reciprocate with actions such as: promoting or ensuring neuronal survival; influencing neuronal differentiation and growth; as well as controlling axon guidance and the conduction of action potentials. The early survival and later maturation of Schwann cell precursors is controlled by neuregulin (Nrg), a neuronally derived signal. Disruption of Nrg signaling between axons and Schwann cells, by directly knocking out either the entire Nrg-1 gene or the genes encoding its receptors, erbB2 and erbB3, leads to an almost complete loss of Schwann cells, followed thereafter by death of the sensory and motor neurons that they support. Later, selective blocking of erbB signaling in non-myelinating Schwann cells produces a progressive sensory neuropathy with subsequent loss of DRG neurons. Reduced Nrg-1 type III expression causes hypomyelination and reduced nerve conduction velocity whereas adding Nrg-1 type II (Glial Growth Factor, GGF) to axon/glia co-cultures inhibits myelination and induces Schwann cell proliferation and migration. Other factors, in particular endothelins, regulate the timing of precursor maturation and Schwann cell generation. In turn, signals derived from Schwann cell precursors or Schwann cells regulate neuronal numbers during development, and axonal caliber, distribution of ion channels and neurofilament phosphorylation in myelinated axons. In addition to providing survival factors to neurons and themselves, and signals that determine axonal architecture, Schwann cells also control the formation of peripheral nerve sheaths. This involves Schwann cell-derived Desert Hedgehog, which directs the transition of mesenchymal cells to form the epithelium-like structure of the perineurium. Schwann cells thus signal not only to themselves but also to the other cellular components within the nerve to act as major regulators of nerve development.


Transcription Factors expressed in Schwann cells

Transcription Factors regulate these events of myelination and the stages in Schwann cell development have been identified. Among these, Oct-6, Krox-20 and Sox-10 have gained prominence in recent years. Oct-6 is a POU-homeodomain protein also known as SCIP and Tst-1. Krox-20 is a zinc finger protein also known as Erg-2. These genes have been shown to act in a genetic cascade: in pro-myelinating Schwann cells (when Schwann cells have established a one-to-one relation with axons but have not yet started to myelinate), Oct-6 expression is greatly increased by yet unknown axon contact signals which leads to the activation of Krox-20. expression of high levels of Krox-20 in turn leads to the activation of the major myelin genes and lipid metabolism genes. Oct-6 is also a strong repressor of myelin specific genes like P0 and MBP. Thus, Oct-6 serves to hold developing cells in an immature phenotype prior to their full differentiation. Oct-6 gene expression is strongly downregulated after the peak of myelination, but is again strongly increased in reactive Schwann cells during nerve regeneration. Oct6 has recently been shown to be involved in a complex modulatory relationship with Ski, another transcription factor in Schwann cells that has similar effects. Krox-20 is restricted to mature Schwann cells during embryogenesis to myelinating Schwann cells and is downregulated following a nerve lesion. A third transcription factor, Sox-10, a HMG-domain protein, is expressed throughout the development of the Schwann cell lineage and possibly acts synergistically with Oct-6 and partially represses Krox-20 activity. Other transcription factors, such as Pax3 and Krox24/Egr1 are expressed in early stages of Schwann cell development and then restricted to non-myelinating Schwann cells. Brn-5 on the other hand is a transcription factor that is stably expressed in the adult myelinating Schwann cell, but virtually absent during pro-myelination. Following nerve injury, when glial growth factor (GGF) levels are elevated in the distal nerve, Brn-5 expression disappears, and SCIP is re-expressed.