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//MECHANISMS OF NEURAL DEVELOPMENT

MECHANISMS OF NEURAL DEVELOPMENT

For more than a century the mechanisms that operate during the development of the nervous system have been studied experimentally. While much has been established, answers to many fundamental questions still remain obscure. In recent years, significant advances in our understanding of the development of vertebrates have come from work on amphibian, chicken, mouse and fish embryos, using a combination of genetic, embryological, biochemical and molecular techniques to elucidate the mechanisms that regulate the behaviour of early neural populations.

The CNS has a fundamental structure of layers and cells, which are all derived from a pluripotential neuroepithelium. Developing neurones produce axons which traverse great distances to reach their target organs. Within the CNS, they form myriad connections with other neurons in response to locally secreted cues.

HISTOGENESIS OF THE NEURAL TUBE

The wall of the early neural tube consists of an internal ventricular zone (sometimes termed the germinal matrix) abutting the central lumen. It contains the nucleated parts of the pseudostratified columnar neuroepithelial cells and rounded cells undergoing mitosis. The early ventricular zone also contains a population of radial glial cells whose processes pass from the ventricular surface to the pial surface, thus forming the internal and external glia limitans (glial limiting membrane). As development proceeds the early pseudostratified epithelium proliferates and an outer layer, the marginal zone, devoid of nuclei but containing the external cytoplasmic processes of cells, is delineated. Subsequently a middle, mantle layer (intermediate zone) forms as the newly formed neurones migrate ventriculofugally from the ventricular zone (see Fig. 24.5).

Most CNS cells are produced in the proliferative zone adjacent to the future ventricular system, and in some regions this area is the only actively mitotic zone. According to the monophyletic theory of neurogenesis it is assumed to produce all cell types. The early neural epithelium, including the deeply placed ventricular mitotic zone, consists of a homogeneous population of pluripotent cells whose varying appearances reflect different phases in a proliferative cycle. The ventricular zone is considered to be populated by a single basic type of progenitor cell and to exhibit three phases. The cells show an ‘elevator movement’ as they pass through a complete mitotic cycle, progressively approaching and then receding from the internal limiting membrane (Fig. 24.15). DNA replication occurs while the cells are extended and their nuclei approach the pial surface; they then enter a premitotic resting period while the cells shorten and their nuclei pass back towards the ventricular surface. The cells now become rounded close to the internal limiting membrane and undergo mitosis. They then elongate and their nuclei move towards the outer edge during the postmitotic resting period, after which DNA synthesis commences once more and the cycle is repeated. The cells so formed may then either start another proliferative cycle or migrate outwards (i.e. radially) and differentiate into neurones as they approach and enter the adjacent stratum. This differentiation may be initiated as they pass outwards during the postmitotic resting period. The proliferative cycle continues with the production of clones of neurones and glioblasts. This sequence of events has been called inter-kinetic nuclear migration: it eventually declines. At the last division two postmitotic daughter cells are produced and they differentiate at the ventricular surface into ependyma.

  

Fig. 24.15  The cell cycle in the ventricular zone of the developing neural tube. The nuclei of the proliferating stem cells show interkinetic migration.
(From Journal of Comparative Neurology 120: 37–42, S Fujita, 1963. Reprinted by permission from Wiley-Liss.)

The progeny of some of these divisions move away from the ventricular zone to form an intermediate zone of neurones. The early spinal cord and much of the brain stem shows only these three main layers, i.e. ventricular, intermediate and marginal zones. However, in the telencephalon the region of cellular proliferation extends deeper than the ventricular zone where the escalator movement of interkinetic migration is seen, and a subventricular zone appears between the ventricular and intermediate layers (Fig. 24.15). Here cells continue to multiply to provide further generations of neurones and glia which subsequently migrate into the intermediate and marginal zones. In some regions of the nervous system (e.g. the cerebellar cortex) some mitotic subventricular stem cells migrate across the entire neural wall to form a subpial population, and establish a new zone of cell division and differentiation. Many cells formed in this site remain subpial in position, but others migrate back towards the ventricle through the developing nervous tissue, and finish their migrations in various definitive sites where they differentiate into neurones or macroglial cells. In the cerebral hemispheres, a zone termed the cortical plate is formed outside the intermediate zone by radially migrating cells from the ventricular zone. The most recently formed cells migrate to the outermost layers of the cortical plate, so that earlier formed and migrating cells become subjacent to those migrating later. In the forebrain there is an additional transient stratum deep to the early cortical plate, the subplate zone.

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