MOLECULAR BASIS OF NEURON/GILA INTERACTIONS IN THE CNS

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Neuron-glia interactions play a critical role during the formation of the central nervous system. Glial cells provide the pathway for the migration of postmitotic neurons away from the germinal layers. Neurons influence the proliferation, survival and differentiation of glial cells. A variety of studies have demonstrated that glia and neuronal-derived factors play critical roles in neuronal and glia precursor proliferation and differentiation, but information abut the nature of these signals remains scarce. The long range objective of the proposed research is to understand the molecular mechanisms controlling neuron-glia interactions in the developing mammalian brain. We are studying a new family of growth factors, the neuregulins, which appears to be implicated in mediating neuron- glia interactions in the peripheral and central nervous system. We now have evidence suggesting that neuregulins may play a role in neuron-glia interactions in the developing cerebellum. We have shown that neuregulin receptors, erbB4, is expressed in the radial glial fibers over which these neurons migrate. The expression of these molecules is developmentally regulated, and restricted to the period of granule cell migration. We have also demonstrated that 1) cerebellar astroglia in culture express erbB4, 2) glial erbB4 expression is regulated by extracellular signals, and 3) glial cells response to neuregulin stimulation in the same manner they respond to contact with neurons. These observations suggest that neuregulin may mediate interactions between granule cells and Bergmann glia, and that these interactions may be important for granule cell migration. The work proposed here is directed to elucidate the regulation and functions of neuregulines in the developing central nervous system. The specific aims of the proposed research are: 1) To identify signals cells that regulate the expression of erbB receptors in cerebellar astroglial cells; 2) To determine effects of NRG on Bergmann glial cell biology, and to determine the contribution of NRG to the effects of granule neurons on the glial cells; 3) To determine the role of NRG in granule cell migration. We will study the role of neuregulin in cerebellar granule cell - Bergamann glia interactions in vitro using cellular and molecular techniques. Neuregulin receptors have a wide range of normal biological actions, but are also proto-oncogenes. Therefore, it is likely that alteractions in the function or expression of either ligand or receptors, will be involved in developmental processes that lead to cancer, mental retardation, epilepsy and other central and peripheral nervous system diseases.