Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells

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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. Neural stem cells in the adult subventricular zone are one of the sources of remyelinating oligodendrocytes. These cells are a heterogeneous population that show diverse responses to signaling pathways in the healthy vs demyelinated brain. We have studied one such pool marked by Gli1, which generates remyelinating oligodendrocytes only in response to demyelination. Our previous work showed that the recruitment and differentiation into oligodendrocytes leading to functional recovery is increased substantially by loss of Gli1 in this pool of neural stem cells; however the molecular mechanisms involved in this repair is not known. Through a transcriptomic analysis comparing gene expression in neural stem cells with and without Gli1 expression, we identified the TGFβ1 pathway as a major regulator of remyelination mediated by neural stem cells. However, the effects of TGFβ1 signaling are context dependent and differ with the cell-type, timing and dosage suggesting the presence of specific modulators of the pathway in different cells. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the TGFβ1 pathway, Gpnmb which is highly expressed along with its receptor CD44 in neural stem cells in response to demyelination. In the first aim, we will define the cell-autonomous function of Gpnmb in neural stem cells and its role in remyelination by neural stem cells. In the second aim, we will determine the impact of paracrine Gpnmb signaling through CD44 receptor on remyelination mediated by neural stem cells. In the third aim, we will elucidate the mechanisms of regulation of Gpnmb by TGFβ1 ligand and reciprocal modulation of the TGFβ1 pathway by Gpnmb. For the remyelination studies, we will use the toxin induced models of demyelination. To define the molecular mechanisms of the TGFβ1-Gpnmb signaling pathway, we will utilize in vitro neural stem cell cultures from adult mouse brain. Together, these studies will help identify therapeutic targets for promoting remyelination.