Mechanisms in CNS myelination: Role of PD-Ialpha/ATX

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DESCRIPTION (provided by applicant): Counter-adhesion, mediated by the family of matricellular proteins, has been implicated in the transformation of cells into an intermediate state of adhesion that favors cellular functions related to locomotion. Despite a variety of locomotive events during myelin sheath formation by oligodendrocytes, the involvement of counter-adhesive mechanisms has not been characterized. We hypothesize, based on our preliminary data, that phosphodiesterase-1 alpha/autotaxin [PD-1 alpha/ATX (NPP-2)] is released by oligodendrocytes as a hitherto uncharacterized counter-adhesive component of the extracellular matrix (ECM) that is critically involved in regulating oligodendrocyte adhesion and myelin membrane formation. In specific aim 1, we will investigate the role of metalloproteolytic activities in the generation of soluble oligodendrocyte-derived PD-1 alpha/ATX, since we have shown that the soluble form of this type II transmembrane protein functions as a counter-adhesive molecule and is present during the initial stages of CNS myelination. In specific aim 2, we will determine the extent to which cytoskeleton-related mechanisms, similar to the ones observed for other matricellular proteins, contribute to PD-1 alpha/ATX's counter-adhesive effect toward oligodendrocytes. In these experiments, we will determine the involvement of integrins, the distribution of cytoskeletal proteins and the activation state of Rho-GTPases to PD-1 alpha/ATX-mediated counter-adhesion. In specific aim 3, we will determine the extent to which proper myelin membrane formation is directly dependent on PD-1 alpha/ATX gene expression levels. In these studies we will analyze the effect of PD-1 alpha/ATX over and under expression on the ability of oligodendrocytes to generate myelin membranes in vitro and to myelinate axons in vivo in the brain of the dysmyelinating mouse mutant shiverer. In addition, we will generate and characterize transgenic mice, in which oligodendrocytes over express PD-1 alpha/ATX. Taken together, these studies will provide novel insight into the role of counter-adhesive molecules for oligodendrocyte function and likely provide novel targets for improving therapeutic strategies designed to stimulate remyelination under pathological conditions.