Neural development requires the generation of an enormous diversity of distinct cell types, and the early assumption of individual cell fates in large part controls the subsequent development of the nervous system. A large body of evidence, particularly from work in Drosophila, has suggested that receptor protein-tyrosine kinases (PTKs) and their ligands play a central role in the choice of cell fate, and in the subsequent survival, proliferation, and full differentiation of neural cells. Work over the last year has now demonstrated that the best-studied neurotrophic molecules of vertebrates - nerve growth factor (NGF) and its cousins - exert their effects through a set of closely-related, neural receptor PTKs. We have extended upon these efforts, and have identified six previously unknown receptor PTKs whose expression, like that of the NGF receptors, is largely confined to the nervous system. In this application, we propose to fully characterize the structure of these new receptors, to determine the specific neural cell types in which they are expressed throughout development, and to initiate experiments designed to identify the neurotrophic ligands through which they are activated. We expect that these studies will greatly extend our knowledge of the structure and action of the neurotrophic proteins that control neural cell fate, differentiation, recognition, and synaptogenesis.
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