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Department of Neurology
Mona Freidin, Ph.D.
Assistant Professor of Neurology
SUNY Downstate Medical Center, Brooklyn, NY
Gap junction proteins, with over 20 connexins identified to date, are a large family of homologous integral membrane proteins that form cell-cell channels. Connexins provide a low resistance pathway for the diffusion of small molecules and ions between coupled cells. Xlinked Charcot–Marie–Tooth disease (CMTX1) is an inherited peripheral neuropathy associated with mutations in GJb1, the human gene for the gap junction protein Connexin32 (Cx32). Cx32 is found in the non-compact myelin of the paranodes and Schmidt-Lanterman incisures of myelinated peripheral nerve providing intracellular channels between adjacent myelin loops and a pathway that shortens the radial diffusion of small cell signaling molecules between the Schwann cell (SC) nucleus and adaxonal membrane at least 300 times. The specific signaling pathways in Schwann cells (SCs) that are disrupted by CMTX1 mutations are not known. Key findings in our lab and others suggests that disruption of SC Cx32 expression leads to a loss of SC-mediated processes required for the myelination, maintenance and repair of peripheral nerves in CMTX1. Evidence from both cultured SC and in vivo mouse models predict that interruptions in Cx32 alter not just the myelinated SC, but non-myelinating SC behavior as well. Neonatal and adult SCs from Cx32 knockout (32KO) mice show decreased proliferative responses to stimulation by GGF2 (Glial Growth Factor 2), a member of the neuregulin family of growth factors. Real time PCR studies revealed GGF2 treatment results in differential regulation of Cx45, Cx47, Cx50, and Cx29 with respect to genotype and age. Further real time PCR studies examined changes in connexin gene expression profiles in 32KO peripheral nerves in vivo at different ages during periods of SC proliferation, myelination, and repair. To more directly probe changes in connexin expression in proliferating populations of adult SCs, real time PCR studies compared samples from WT and 32KO transected nerves at 4 post-injury during a period of SC de-differentiation and proliferation. These and related studies will ultimately determine the regulatory features of Cx32 in aging and regenerating peripheral nerves from WT and 32KO mice; identifying and confirming pathways associated with SC cell cycle control, survival, and myelination and expression of Cx32.