During normal brain development, vast numbers of cells must arise from progenitor cells, migrate to their correct final positions, differentiate, and in the case of neurons form appropriate axonal and dendritic connections. Irregularities in any of these events during development can result in neurological disorders, affecting functions from movement to memory and cognition to our very individuality. Recent progress in understanding the genetic basis of these disorders has underscored the importance of studying the fundamental molecular basis of brain development. A number of novel and known genes whose spatio-temporal expression patterns suggest they may play important roles in the ontogeny of the brain have been isolated. The proposed investigations focus on one gene, based on its intriguing expression pattern in the developing CNS and to its similarity to a receptor that is involved in axonal guidance. This gene has been recently been reported by Kang et al. (J. Cell Biol. 143:403 (1998)) and named CDO. CDO is a receptor-like molecule with an extracellular domain of 967 residues with 5 immunoglobulin domains, 3 fibronectin-like domains, one trans-membrane of 26 residues and a cytoplasmic domain of 255 residues. This """"""""5+3"""""""" structure is reminiscent of Robo, a receptor known to be involved in the decision of neurons to cross the midline and make appropriate connections. Preliminary experiments have demonstrated that the application of extra-cellular domain of CDO onto cultured progenitor cells from the cerebral cortex dramatically impacts the development of cells in vitro. These results together with the restricted expression of CDO in the dorsal telencephalon and in cells at the midline in the spinal cord support the hypothesis that CDO can and may play a fundamental role in the development of the CNS. Here, experiments that will assess the effect of the addition or removal of CDO function from cells in vivo and in primary cultures are proposed.
The Specific Aims are: 1) To elucidate the function of CDO in cultured primary cortical cells 2) To determine the function of CDO by assessing the effect of removing gene function in mice 3) To analyze the effect of expressing exogenous CDO in developing mice. These experiments should also contribute to the overall understanding of the signals that are important in the assembly of the nervous system.
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