The long-term goal of these studies is to gain insight into the role of counteradhesive molecules for oligodendrocyte function. Counteradhesion, mediated by the family of matricellular proteins, has been implicated in the transformation of cells into intermediate adhesive states that favor cellular functions related to locomotion. Despite of a variety of locomotive events during myelin sheath formation, the involvement of matricellular proteins has not been characterized. We hypothesize, based on our preliminary data, that phosphodiesterase-Ia/autotaxin [PD-Ia/ATX (NPP-2)] is released by oligodendrocytes as a hitherto uncharacterized matricellular component of the extracellular matrix that regulates the adhesive state of post-migratory oligodendrocytes and consequently determines their process remodeling capacity and thus the overall efficiency of myelin sheath formation. In, specific aim 1, we will investigate the role of metalloproteolytic activities in the generation of soluble, oligodendrocyte-derived PD-Ia/ATX, since it is the soluble form of this type II transmembrane protein that appears functionally active during myelination initiation.
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-Ia/ATX's counteradhesive effect toward oligodendrocytes. In these experiments, we will determine the involvement of functional active integrins, the redistribution of cytoskeletal proteins and the activation of Rho-GTPases for PD-Ia/ATX mediated counteradhesion. In the experiments to specific aim 3, we will determine the extent to which process outgrowth/remodeling and myelin membrane and sheath formation is directly dependent on PDIa/ATX expression levels. In these studies we will analyze PD-Ia/ATX over- and under-expressing oligodendrocytes for their capacity to generate complex process morphologies and myelin membrane structures in vitro and to myelinate axons in vivo in the brain of the dysmyelinating mouse mutant shiverer. In addition, we will characterize transgenic mice, in which oligodendrocytes over-express PD-la/ATX. These studies will provide novel insight into the molecular mechanisms that determine CNS myelination, and they may contribute to the development of novel therapeutic strategies designed to improve remyelination under pathological conditions. ? ?
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