Growth and differentiation in the nervous system are regulated by a complex interplay of genetic and epigenetic factors and signals. Nerve growth factor (NGF) and its cognate receptor can change the pattern of gene expression in responsive cells at specific stages in development. In this proposal, we plan to investigate the expression of the NGF receptor gene in the nervous system and to correlate structural features of the receptor with its function. In preliminary experiments, we have used a cloned human cDNA probe to detect tissue specific and developmentally regulated transcription of the NGF receptor gene. We have also deciphered the entire amino acid sequence of the receptor. This proposal describes experiments to follow the developmental expression of the NGF receptor in the peripheral and central nervous systems and also in nonneuronal cells which express the receptor. Using recombinant DNA, in vitro mutagenesis, and gene transfer technology with cultured cells, primary nerve cells, and transgenic mice, we wish to identify which regions of the receptor molecule are important for the functioning of NGF. The ability to introduce specific wild-type receptor gene and in vitro constructed mutants into appropriate cells affords the unique opportunity to discern which sequences are essential for various levels of expression. Further, our studies may provide information concerning the molecular basis for developmental and neurodegenerative disorders such as familial dysautonomia and Alzheimer's.
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