Oligodendrocytes (OLs) are the cells that myelinate axons in the central nervous system. OL development begins with ventricular zone (VZ) progenitors that give rise to oligodendrocyte progenitor cells (OPCs), which subsequently proliferate, migrate, and differentiate into mature myelinating OLs. This multistep process requires precise regulation of intracellular signaling. The overall goal of this proposal is to identify cooperating signaling pathways that affect distinct stages of OL development. Using mouse genetics, we found that the intracellular protein tyrosine phosphatase Shp2, a RASopathy gene that has a positive role in the RAS/MAPK pathway, is a key regulator of multiple stages of OL development. Specifically, we found that altering Shp2 phosphatase activity impacts the generation of OPCs and also OL myelination. Interestingly, downstream of Shp2 function, we detect changes in MAPK and WNT signaling. Here we propose to test the hypothesis that altering the balance of Shp2 phosphatase activity results in changes in MAPK and WNT pathway activation that results in abnormal OPC generation and OL myelination. In the first aim, we will test if Shp2 phosphatase activity and/or adaptor function(s), independent of phosphatase activity, are critical in OPC/OLs and determine if the OPC and myelination abnormalities caused by altered Shp2 phosphatase activity impacts animal behaviors. In the second aim, we will identify MAPK pathway dependent and independent roles downstream of Shp2 signaling during OL development. In the third aim, we will identify the role of the WNT pathway in abnormal OL development caused by Shp2 RASopathy mutations. These studies will identify the specific roles of MAPK versus WNT signaling downstream of altered Shp2 function OL development, and provide a new understanding of the complex relationships between multiple signaling pathways during OL development.

Public Health Relevance

The research described in this proposal utilizes complex mouse genetics to examine cooperating signaling pathways that affect distinct stages of oligodendroctye development. Specifically, we will test if altered Shp2 phosphatase activity from Shp2 RASopathy mutations impacts distinct stages oligodendrocyte development. In addition, we will identify the specific roles of MAPK versus WNT signaling downstream of altered Shp2 function in OPC/OL development. We will determine if aberrant MAPK and/or WNT signaling from elevated Shp2 phosphatase activity causes oligodendrocyte abnormalities. These studies will further our understanding of the cell signaling mechanisms necessary for the generation of distinct stages of oligodendrocyte development and also allow us to better understand the physiological role of Shp2 in brain development, as well as the mechanisms underlying the pathophysiology of Shp2 RASopathy mutations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Morris, Jill A
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Cincinnati Children's Hospital Medical Center
United States
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