Molecular and genetic regulation of myelin capacity in the CNS

PROJECT SUMMARY The myelin sheath is a multilayered membrane generated by specialized glial cells called oligodendrocytes (OLs) that iteratively spiral their plasma membranes around axon segments in the central nervous system (CNS) of vertebrates. Myelination serves to increase the conduction velocity of action potentials, and OLs provide trophic support that is vital for neuronal survival. The importance of myelin in human health is underscored in diseases in which it is disrupted, like leukodystrophies and multiple sclerosis. Despite the importance of myelin, we lack a complete understanding of the molecular and genetic mechanisms that govern OL development and myelination; additionally therapeutic strategies to promote remyelination are sorely lacking. This proposal focuses on two critical regulators of OL development and myelination: Fbxw7 and Myrf. Loss of Fbxw7, a ubiquitin ligase component, in animal models leads to increased amounts of myelin formation, whereas loss of Myrf results in a lack of myelination. Fbxw7 targets Myrf for degradation, and we hypothesize that Fbxw7 functions to limit myelination in the CNS by acting, at least in part, by controlling Myrf levels. In this proposal, we will employ a synergistic combination of zebrafish and mouse models to: 1) define the cellular mechanisms by which Fbxw7 regulates OL development, myelination, and myelin homeostasis; 2) determine the role of Fbxw7 in remyelination; 3) Define the cadre of myelin-promoting Fbxw7 targets in OLs, with a particular focus on Fbxw7’s regulation of Myrf. These experiments will enhance our understanding of OL biology and may lay the foundation for future therapeutics that stimulate myelin repair in humans.