DEVELOPMENTAL REGULATION OF THE NERVE GROWTH FACTOR RECEPTOR GENE

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Cell survival and differentiation in the nervous system are mediated by many polypeptide growth factors, of which nerve growth factor (NGF) has provided the most compelling evidence for a physiological role during development. NGF interacts on responsive neurons with two different receptor molecules, the low affinity (p75NGFR) NGF receptor and the product of the proto-oncogene trk, p140trk. Although these two receptors are believed to be involved in mediating neurotrophic effects and to be coexpressed on responsive cells, regulation of expression of these NGF receptor genes is not understood. We intend to use gene transfer techniques and transgenic mice to define the DNA elements required for proper, neuronal expression of both p75NGFR and p140trk. NGF's biological actions are likely to depend upon appropriate regulation and stoichiometry of the two receptors in the correct cell types. Therefore, these studies will allow us to understand the molecular requirements for neurotrophic action in the nervous system, and will suggest new directions for studying neurodegenerative diseases such as Parkinson's and Alzheimer's dementia.