Developmental function neuronal guidance

The vertebrate brain develops from the embryonic neuroectoderm that lies above the notochord and gives rise to the entire nervous system. The notochord induces neuroectodermal cells to generate neural stem cells and form the neural plate, which in turn forms the neural tube, from which the brain and spinal cord are derived. The neural precursor cells of the neural tube give rise to both neurones and glia in response to multiple inductive signals produced by the notochord, floor plate, roof plate, dorsal ectoderm and somites; for example, retinoic acid, fibrob-last growth factor, bone morphogenetic proteins and sonic hedgehog. Inductive signals regulate transcription factors and gene expression, including the home-obox (Hox) genes, which influence the development of the neural tube into the major brain regions; forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon). The first neural cells to develop are radial glia. After this, neural precursors in the ventricular zone (VZ) and subventricular zone

(SVZ) immediately surrounding the lumen of the neural tube migrate to their final destinations and give rise to the enormously diverse range of neurones and glia found in the adult brain (Figure 7.2).

An important function of foetal radial glial cells is to provide the scaffolding along which neural precursors migrate (Figure 7.2). Not all neurones migrate along radial glia, but it is always the case where neurones are organized in layers, such as the cerebellum, hippocampus, cerebral cortex and spinal cord. In the cerebral cortex, for example, bipolar postmitotic neurones migrate several millimetres from the ventricular zone to the pia along the processes of radial glia; the cerebral cortex is formed inside out, whereby the innermost layers are formed first, and the superficial layers are formed later by neurones that migrate through the older cells. In the cerebellum, granule cells migrate along Bergmann glia, which are derived from radial glia. Migration depends on recognition, adhesion and neurone-glial interactions, which are under the influence of cell membrane bound molecules,

Glial Cell Migration

Figure 7.2 Radial glial cells form a scaffold that assists neuronal migration in the developing nervous system. Radial glial cells extend their processes from the ventricular zone (VZ) and subventricular zone (SVZ), where neural progenitors reside, towards the pia. Neuronal precursors attach to the radial glial cells and migrate along their processes towards their final destination. Numerous reciprocal factors released by both neurones and glia regulate the processes of mutual recognition, attraction, adhesion, migration and final repulsion

Figure 7.2 Radial glial cells form a scaffold that assists neuronal migration in the developing nervous system. Radial glial cells extend their processes from the ventricular zone (VZ) and subventricular zone (SVZ), where neural progenitors reside, towards the pia. Neuronal precursors attach to the radial glial cells and migrate along their processes towards their final destination. Numerous reciprocal factors released by both neurones and glia regulate the processes of mutual recognition, attraction, adhesion, migration and final repulsion and diffusible and extracellular matrix molecules. Although the specific signals are not fully resolved, they include laminin-integrin interactions and neuregulin, which is expressed by migrating neurones and interacts with glial ErbB receptors. Subsequently, foetal radial glia disappear and transform into astrocytes; remnants of radial glia persist in the adult brain where they can generate olfactory and hippocampal neurones.

After neurones reach their final sites, they extend axons, which in some cases grow for considerable distances and have to cross the brain midline (decussate) to reach their synaptic targets. Channels formed by astrocytes provide a mechanical and guidance substrate for axon growth. In the corpus callosum, for example, astrocytes form a bridge (the glial sling) that connects left and right sides of the developing telencephalon. The ability of astrocytes to support axon growth decreases with age; embryonic astrocytes strongly support axon growth, whereas mature astrocytes inhibit axon growth - hence, the astroglial scar that forms following damage to the adult CNS is a major barrier to axon regeneration. Astrocytes produce a number of membrane bound and extracellular matrix molecules that serve as molecular cues for axon growth. These are generally considered to act by activating receptors on axonal growth cones to regulate process outgrowth; for example, N-cadherins and fibroblast growth factor receptors mediate neurite outgrowth by increased intracellular calcium in the growth cone. Astroglial laminin-1 is an excellent growth substrate for axons, and decussation of axons at the optic chiasm is dependent on laminin-1 and chondroitin sulphate proteoglycans produced at the glial boundary. Growth inhibitory molecules such as sempaphorins and ephrins also play important roles as guidance cues by regulating growth cone collapse.

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