During development of the vertebrate nervous system, nerve growth factor (NGF) is crucially required for the proper maintenance and survival of sympathetic and sensory neurons, and probably cholinergic neurons in the basal forebrain. Although NGF was the first growth factor to be identified, its mode of action is not well understood, except that its actions are first initiated by interaction with a high affinity cell surface receptor. This project is directed at the role of the NGF receptor in initiating cellular resoponses to NGF. The cloning of the gene for the human NGF receptor has provided a probe to investigate the events that follow the binding of NGF to responsive cells. Using a combined molecular and biochemical approach, the high affinity NGF receptor will be defined with respect to ligand binding domain, internalization, and potential interaction with guanine nucleotide binding (G) proteins. The difference between high and low affinity forms of the receptor will be clarified by gene transfer into cells of neural crest origin and by membrane fusion experiments. Responses to NGF such as neurite outgrowth, c-fos oncogene induction, and S6 phosphorylation will be assessed in cell lines containing mutant NGF receptors. Physical-chemical characterization of receptor-associated proteins will define auxillary molecules that regulate receptor affinity and participate in transducing the NGF signal. Chimeric receptors will be constructed to test whether domains of the receptor can function independently and can still take part in transmembrane signal transduction. The analysis of the role of the NGF receptor in the mechanism of action of NGF will advance our understanding of the structure and function of growth factor receptors and the molecular requirements for survival and maintenance of specific classes of neuronal cells. Abnormal growth factor action has been associated with several disease states, including neoplastic transformation. Defects in NGF function have been implicated in several neurological disorders, including familial dysautonomia, Alzheimer's dementia, and neurofibromatosis.
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