TROPHIC FACTOR CONTROL OF NEURON PRODUCTION AND SURVIVAL

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Precise regulation of neuron number is a hallmark of nervous system development. neuron number appears to be achieved by a balance of neuron production and neuron survival during development. Polypeptide growth factors are known to mediate neuron survival in many areas of the nervous system, but their role in controlling neuron production is undetermined. The goal of the proposed research is to determine how the mitogenic and survival-promoting activities of polypeptide growth factors interact to regulate neuron number during nervous system development. To accomplish this, regulation of neurogenesis and neuron survival will be examined in a regenerating sensory epithelium, the olfactory epithelium (OE) of the mouse. Preliminary studies indicate that members of 2 families of polypeptide growth factors may be important in governing neuron production and survival in OE. Analysis of RNA from embryonic OE has demonstrated the presence of tyrosine kinase Fibroblast Growth Factor Receptors. In support of this idea, basic Fibroblast Growth Factor (bFGF) appears to increase proliferation of olfactory neuron precursors in OE tissue cultures, suggesting a role of FGFs in regulating neurogenesis. Affinity crosslinking studies indicate that receptors for at least 2 Neurotrophins (NTs), Brain Derived Neurotrophic Factor and Neurotrophin-3, are present in OE. Both in vivo and in vitro experiments will be performed to determine how the actions of FGFs and NTs regulate neuron number in the OE. Biological activities of NTs and FGFs will be determined by assessing their effects on defined OE cell populations, using new procedures for purifying and culturing these cells from outbred and transgenic mice. Cellular targets of trophic factor action will be defined both by functional assays and by examining expression of growth factor receptors in identified cells, using molecular markers specific for cells at different developmental stages in the OE neurogenic pathway. To assess in vivo roles of trophic factors found to be active in vitro, expression of factors in OE, its supporting tissue, and its synaptic target (olfactory bulb) will be examined. In vivo replacement studies will be performed to determine whether specific factors, identified in vitro, can prevent or ameliorate surgically-induced degeneration of olfactory receptor neurons. This work will aid in the understanding and treatment of developmental disorders of the nervous system, such as neural tube defects, by providing information about how neuron number is controlled during development. By determining whether administration of specific trophic factors can prevent neuronal degeneration, this work may aid in the development of therapies for both neurodegenerative diseases and trauma-induced degeneration of neurons.