Axons regulate the proliferation, survival and differentiation of Schwann cells. Neuregulin- I (NRG- 1), a family of neuronal growth factors, has an established and crucial role in the early events of Schwann cell development, promoting Schwann cell maturation, proliferation and survival. Neuregulin receptors, members of the erbB family of receptor tyrosine kinases, are expressed by Schwann cells. Following ligand binding, they undergo autophosphorylation and activate intracellular signaling pathways, notably investigator 3-kinase which we have shown is required for these early events. In this proposal, we will investigate whether NRG- 1 and the erbB receptors, exclusively mediate the initial interactions of axons and Schwann cells or whether they also mediate later interactions, including myelin and basal lamina (BL) and node of Ranvier formation. To investigate the role of NRG- 1 in these later events of development, we will coculture mature Schwann cells with neurons isolated from mice with either a conditional, neuron-specific knockout of NRG-1 or a knockout of the CRD-NRG-l isoform. We are particular interested in whether nrg- 1-I- neurons can still induce Schwann cell proliferation and survival and promote normal myelin and BL formation. We have recently found that erbB2 and several candidate interacting proteins, are enormously enriched in the Schwann cell microvilli which contact the nodal axolemma. To elucidate the signifance of this finding for local signaling and node organization, we will characterize the time course of its accumulation and its precise localization in the microvilli, determine whether erbB2 is complexed to and/or activates several candidate proteins in the microvilli and examine whether erbB2 regulates microvilli formation and nodal organization. Finally, we have found that MAP kinase and P1 3-kinase activation are activated not only during development, but also shortly after axotomy and NRG-induced demyelination. To investigate the role of MAP kinase and investigator 3-kinase activation during Wallerian degeneration and demyelination, we will examine whether activation of these pathways is a feature of demyelination in vivo, examine the effects of blocking their activation using pharmacologic inhibitors during Wallerian degeneration in vitro and determine whether the sequence of events during Wallenan degeneration is altered in cultures from NRG- 1 knockouts or in cultures treated with erbB2/e3rbB3-Fc, which inhibits NRG- 1 signaling.
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