The long-term goal of this project is to better understand the molecular mechanisms that determine central nervous system myelination during normal development as an approach to improve strategies for myelin repair under pathological, de-/dysmyelinating conditions, such as they occur in hereditary leukodystrophies. Since repair of the myelin sheath under such pathological conditions still remains limited, yet to be characterized molecular mechanisms are likely to significantly contribute to proper myelination. These mechanisms include those that are mediated by proteins derived from the myelin forming cells of the CNS, oligodendrocytes. The central hypothesis for the proposed studies is that soluble, oligodendrocyte-derived phosphodiesterase-I/autotaxin (PD-I alpha/ATX) is an essential component of a currently uncharacterized molecular process that regulates proper CNS myelination. PD-I alpha/ATX is released by differentiated oligodendrocytes at the developmental time-point at which oligodendrocytes are actively involved in the generation of the myelin sheath. The investigator's preliminary data indicate that the release of PD-I alpha/ATX is regulated by proteolytic cleavage. Accordingly, Specific Aim 1 will study the molecular mechanism that regulates the generation of soluble, oligodendrocyte-derived PD-I alpha/ATX. Since the primary sequence of PD-I-alpha/ATX reveals structural domains that are likely to be involved in cell-cell and/or cell-extracellular matrix interactions, potential PD-I alpha/ATX-interacting molecules of the CNS will be identified in the studies of Specific Aim 2 by using biochemical as well as molecular biological approaches. Taken together, these studies will provide novel insights into PD-I alpha/ATX-mediated events that control CNS myelination during development and that may stimulate remyelination in de-/dysmyelinating diseases.
