Mechanisms of membrane protein trafficking and AKT/mTOR signaling that promote myelin sheath stability and growth

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Project Summary Myelin sheaths are built through a dynamic process of axonal adhesion and membrane biogenesis to form a compact, multilamellar structure. Interestingly, only a fraction of sheaths that initiate at the onset of myelination will stabilize and mature to form compact myelin. We know that axonal adhesion proteins are important for determining sheath stability. However, there is a fundamental gap in our understanding of how these molecules are maintained at the myelin/axolemma interface during the dynamic process of myelin wrapping. Additionally, AKT/mTOR signaling is an important driver of membrane biogenesis in oligodendrocytes. However, we do not know whether AKT/mTOR signaling drives ensheathment events or rather this pathway acts downstream of axonal adhesion. Therefore, our objective here is to investigate the mechanisms for trafficking myelin/axonal adhesion molecules and for activating AKT/mTOR signaling to promote sheath stabilization and growth. In aim 1, we will use a combination of genetic manipulations, in vivo live-cell imaging, and biochemistry to investigate the mechanisms of membrane trafficking that localize MAG to the axolemma interface. In aim 2 we will use a MAG knockout fish line to perform genetic epistasis experiments to determine if the AKT/mTOR pathway promotes sheath stabilization downstream of axonal adhesion. Together this project will elucidate how AKT/mTOR signaling interfaces with membrane protein trafficking pathways to build a myelin sheath.