The production of myelin, the ensheathing membrane that is essential for normal brain development and function, is tightly regulated. Bidirectional interactions between axons and myelinating glia determine the amount of myelin that is generated. Intracellular signals must direct the necessary increase in myelin gene expression required for proper myelination and also establish when the ensheathing cell should decrease myelin production and shift to myelin maintenance. Akt signaling has been demonstrated to drive myelination in both the peripheral and central nervous systems. The regulation of central nervous system (CNS) myelination, however, is not well understood. The current proposal investigates the signaling mechanisms that regulate CNS myelination. We will focus on the inhibitory signals that downregulate normal myelination after axons have been appropriately wrapped. In this regard, we propose to investigate the role of negative regulators of Akt signaling in oligodendrocytes, the myelinating cells of the CNS. We will focus on the protein tyrosine phosphatase Shp2, which may act as a brake to active myelination. We will also examine the role of Shp2 during remyelination, the regenerative process of restoring myelin to axons after a demyelinating injury. For these studies, we will utilize transgenic Cre/lox mouse technology in order to induce the knockout of Shp2 specifically in oligodendrocytes. Having a more precise understanding of the signaling mechanisms regulating myelination could help to facilitate the design of more effective treatments for acquired myelin diseases, such as multiple sclerosis. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a common neurodegenerative disease that often leads to substantial physical and cognitive disability in those affected due to repeated destruction of myelin, the ensheathing membrane that wraps axons and is essential for proper nervous system function. Most current therapies for MS focus on reducing or eliminating the immune attack on the myelin, but the long-term central nervous system (CNS) damage remains. The goal of this proposal is to understand the molecular signals that regulate the activity of oligodendrocytes, the myelin producing cells of the CNS, a is pivotal step in developing new therapies aimed at improving myelin repair in acquired myelin diseases, such as MS.