Function and Regulation of Intercellular Communication

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DESCRIPTION (provided by applicant): Previously, we showed that mutations in connexin32 (Cx32) cause a form of Charcot-Marie-Tooth disease, a demyelinating neuropathy of the peripheral nervous system (PNS). In addition, we showed in mouse knockout studies Cx32 and Cx47 provide redundant functions necessary for normal myelination in the central nervous system (CNS), an observation confirmed by the recent discovery that Cx47 mutations cause Pelizaeus-Merzbacher-Like disease (PMLD), characterized by abnormalities in CNS myelin. Thus, maintenance of myelin in both CNS and PNS requires connexin expression. However, it is not at all clear how oligodendrocytes and Schwann cells use connexins and why they are critical for normal myelination. We propose to define the separate and interacting roles of connexins in myelination and why mutations cause disease using a combination of targeted gene ablation and functional analysis of connexin channel activity. '.