ABSTRACT Loss of oligodendrocytes gives rise to demyelination, ultimately resulting in axonal degeneration and debilitating clinical outcomes in diseases like Multiple Sclerosis. While remyelination can prevent neurodegeneration, there are currently no approved therapies for promoting remyelination. Thus, there is an urgent need to identify factors that control remyelination. Oligodendrocyte progenitor cells (OPCs) in the adult brain are one of the key sources of remyelinating oligodendrocytes. However in chronic demyelination, they are inefficient for remyelination due to depletion and/or a block in their maturation. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the 7*)? pathway, Gpnmb which is highly expressed along with its receptor CD44 in response to demyelination. Gpnmb is a transmembrane protein that is cleaved by proteases into an intracellular domain (Gpnmb-ICD) and an ectodomain (Gpnmb-ECD). While Gpnmb-ICD can signal intrinsically by translocating to the nucleus, the released Gpnmb-ECD functions as an autocrine or paracrine signal by interacting with CD44 receptor in the same cell or a neighboring cell respectively. In the first aim, we will define the cell-autonomous function of Gpnmb in oligodendrocyte progenitor cells and in the second aim, we will determine the combined effect of intrinsic and extrinsic Gpnmb signaling on OPCs following cuprizone induced demyelination. Together, these studies will not only help elucidate the molecular mechanisms involved in maturation of adult OPCs but may also identify therapeutic targets for promoting remyelination.