The principle goal of the proposed studies is to elucidate the role of the CD44 family of transmembrane glycoproteins in perpheral nerves during development and following injury. Peripheral nerve development and maintenance require tightly regulated interactions between axons and Schwann cells. Schwann cell survival, proliferation and differentiation are influenced by axon-derived signals. One key signal is glial growth factor (GGF), which activates heterodimers of the receptor protein tyrosine kinases erbB2 and erbB3 in Schwann cells. GGF and its receptors have also been implicated in Wallerian degeneration, a process that occurs following nerve injury and which includes that induction of Schwann cell proliferation. The means by which GGF and related axon-derived signals promote erbB2-erbB3 heterodimerization and kinase activity are unclear. Our central hypothesis is that CD44 proteins are required for GGF signaling and in Schwann cell survival, proliferation and differentiation. CD44 has been implicated in cell-cell and cell- matrix interactions, and in growth factor presentation to high affinity cell surface receptors. Our preliminary data indicate the CD44 is essential for erbB2-erbB3 heterodimerization in Schwann cells, and that inhibition of CD44 expression results in Schwann cell apoptosis. We also found that CD44 is expressed in developing peripheral nerve at high levels when erbB2 expression is high and during active Schwann cell proliferation. We propose that CD44 acts by facilitating the interaction between axon- derived GGF and erbB receptors on the Schwann cell surface. We will test this notion experimentally with the following specific aims: (1) To ascertain whether CD44 acts as a low affinity GGF receptor; (2) To define the structural domains of CD44 that mediate interactions with ErbB2 and ErbB3 using cells expressing mutant CD44 proteins; (3) To determine if CD44 is required for Schwann cell survival, proliferation and/or differentiation during peripheral nerve development and Wallerian degeneration by comparing wild type mice and trasngenic mice whose Scwann cells lack CD44. Understanding how CD44 mediates the GGF-erbB2-erbB3 signaling complex will provide insight into the molecular mechanisms underlying normal peripheral nerve development, and may contribute significantly to our understanding of numerous conditions and diseases where axonal degeneration occurs, including nerve trauma, spinal cord injuries, and peripheral neuropathies.
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