In the peripheral nervous system, Schwann cells (SCs) extend plasma membrane processes to wrap axons with myelin. Myelin sheath thickness and internodal distance are important determinants of nerve conduction velocity, which is critical for precise control of timing impulse conduction. Acquired myelin disorders include nerve injury, Carpal tunnel syndrome, immune-mediated demyelinating diseases, multiple sclerosis (MS) and Guillian-Barre syndrome, some of which are known to affect war veterans. Remyelination or myelin repair is critical for the recovery from myelin disorders. However, underlying mechanisms remain poorly understood. Recent studies demonstrate that neuregulin 1 (NRG1), which is known to be critical for myelin development in the peripheral nervous system, also plays an important role in remyelination after nerve injury. In Preliminary Results, we found that mutant mice of Erbin, a protein that interacts with the NRG1 receptor ErbB2, are impaired in remyelination of axons of injured nerves and slow in functional recovery. Moreover, Erbin expression was induced in injured sciatic nerves, in advance of elevation in ErbB2. Remarkably, this increase was blocked in Erbin null mice. These results identified Erbin as a novel regulator of remyelination and are in consistent with the hypothesis that Erbin promotes remyelination of regenerated axons by regulating NRG1/ErbB2 signaling. To test this hypothesis, we will 1) characterize remyelination and NRG1 signaling in Erbin mutant mice where Erbin is truncated with the PDZ domain and thus is unable to interact with ErbB2, to determine whether the interaction between Erbin and ErbB2 is important for remyelination;2) to understand cellular mechanisms by which Erbin regulates remyelination;and 3) to investigate how Erbin regulates ErbB2 stability and trafficking in SCs. Successful completion of these aims will elucidate novel mechanisms that govern SC behavior during nerve repair and provide insight into how Erbin regulates NRG1 signaling. Results may contribute to a better understanding of peripheral neuropathies of war veterans and to development of potential targets for therapy and diagnosis.
This proposal is aimed at delineating the cellular and molecular mechanisms for Erbin to regulate remyelination. Successful completion of the proposed research could lead to elucidation of novel mechanisms in nerve regeneration after injury. Results may also contribute to a better understanding of peripheral neuropathies of war veterans and development of potential targets for therapy and diagnosis.