CONTROL OF CELL MIGRATION IN DEVELOPING BRAIN

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The goals of this research are to reach a better understanding of the sequence of events which lead a young neuron from the proliferative zones to its proper position in the mature brain, to begin to understand how specific genes might contribute to (and/or disrupt) the migratory process, and to analyze the capacity of neurons which are in the wrong position to make adjustments in their connectivity while differentiating. The approach to be taken will be to exploit the existence of mutations in the mouse which disrupt the migration of neurons in the developing central nervous system and thereby produce malformations of the adult brain in which specific populations of neurons reside in abnormal positions. Specific aims of this project are: 1) to determine the development processes modified by four different genetic defects which affect the position ultimately assumed by young neurons during their migration from the proliferative zone to their final position during the development of the central nervous system, and 2) to analyze in the mature central nervous system the changes in the axonal and dendritic arborizations of neurons which migrate to the wrong position during the developmental period. Experiments will be conducted which will: 1) explore the relative contributions of the migrating neurons themselves, of radial glial cells, of previously generated neurons, and of axons from adjacent structures in influencing the "stopping" point along the migratory trajectory of a young neuron, 2) analyze the morphological differences between neurons which have reached a "wrong" position and those which have assumed the "correct" position, and 3) clarify some aspects of the genetics of the experimental situations. This work is significant because of its contribution to the understanding of cell migration during the development of the central nervous system.