The long-range goal of this research is to understand the molecular mechanisms of how axonal injury in the peripheral nervous system induces Schwann cells to form a micro-environment supportive of axonal regeneration. A key event in this process is the dedifferentiation and proliferation of the mitotically quiescent Schwann cells of adult peripheral nerve. Although the identity of the molecular signal(s) triggering the Schwann cell response to axonal injury is unknown, members of the neuregulin (NRG) family of growth and differentiation factors are likely candidates as these molecules are potent Schwann cell mitogens and differentiation factors in vitro. Based on our preliminary data, we hypothesize that NRGs, initially released from the injured axon and subsequently produced by the Schwann cells and macrophages, critically regulate axonal regeneration via induction of Schwann cell proliferation. To test our hypothesis, we propose an integrated approach in which recombinant NRG proteins and specific NRG inhibitors developed in our laboratory will be used to establish whether alpha- and/or beta-NRGs are both necessary and sufficient for postaxotomy Schwann cell proliferation in vivo. We will determine: 1) whether soluble, biologically active forms of the predominant beta- and alpha-NRGs expressed in axotomized nerve are sufficient for Schwann cell dedifferentiation and proliferation in vivo; 2) whether NRGs are necessary for postaxotomy Schwann cell dedifferentiation and proliferation; and 3) whether NRGs activate specific intracellular signaling pathways mediating Schwann cell proliferation and whether beta- and alpha-NRGs differ in their ability to activate these pro-proliferative signaling pathways. The proposed research plan represents a natural progression of our work to date and will provide valuable insights into the molecular mechanisms underlying axonal regeneration in traumatic nerve injury and primary axonopathies as well as having important implications for nervous system neoplasia.
