Regulation of myelination by myosin II-mediated mechanotransduction

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DESCRIPTION (provided by applicant): In diseases such as Multiple Sclerosis in the central (CNS) and Guilain-Barre Syndrome in the peripheral (PNS) nervous system, loss of myelin results in conduction block along affected axons and underlies the clinical deficits characteristic of these disorders. Recovery of neural function is associated with remyelination, which not only restores nerve conduction, but also re-establish the normal molecular organization of the myelinated axon. Although therapies are available that address the inflammatory attack on CNS and PNS myelin, there are currently no treatments designed to directly target the efficiency of myelin repair and the return of nerve function. We identified non-muscle myosin II (NMII) as a novel key regulator of glial cell differentiation and myelin formation in both the PNS and the CNS. NMII is necessary for the ensheathment of axons by Schwann cells, and its inhibition impairs their morphological differentiation and ability to form myelin. By contrast, inhibition of NMII in oligodendrocytes promotes cell branching and enhances myelin formation. The molecular mechanisms behind these remarkably opposite effects are currently unknown, but if understood might provide novel therapeutic targets to promote repair of demyelinated nerves and restore nerve function. In this application we propose to test the hypothesis that the ability of Schwann cells and oligodendrocytes to sense and respond to the unique mechanical properties of their environment plays a major role in the differential response of these cells to NMII inhibition. Of particular relevance for this application are the observations that the extent f cell branching and the lineage commitment of undifferentiated cells can be regulated by changes in the extracellular matrix (ECM) elasticity in a NMII-dependant manner. In Aim#1 we will characterize how differences in ECM elasticity affect glial cell morphology and differentiatio using a culture system that allows the control of substrate elasticity and determine the direct rol of NMII in mediating these effects by performing loss and gain of function experiments. In Aim#2 we will establish the direct mechanistic link between process extension and downregulation of NMII activity downstream of Rho/ROCK, using a combination of live-cell imaging and loss and gain of function experiment. Finally in Aim#3 we will directly examine the relevance of NMII for myelin development and remyelination in vivo using mice in which NMIIB has been conditionally ablated in myelinating CNS and PNS glia. The long-term goal of our research is to understand the cytoskeletal mechanisms regulating Schwann cell and oligodendrocyte differentiation as a way to identify novel therapeutic targets to promote myelin repair and recovery of nerve function.