Mechanisms of myelin membrane expansion

Myelin is the protective covering that surrounds nerve fibers to accelerate communication between different parts of the nervous system. Damage to myelin occurs in diseases such as multiple sclerosis, which compromises nerve signaling and impairs motor and cognitive function. Myelin forms from a cell type called an oligodendrocyte, which has to first expand massively in size and then flatten out to make dozens of wraps to cover a nerve fiber. When myelin is damaged in adults, new oligodendrocytes appear but fail to re-wrap the nerve fiber over time. Oligodendrocyte expansion for wrapping appears to be a frequent point of failure in the brain?s natural capacity to repair myelin. In this project, I will identify cellular pathways responsible for making oligodendrocytes expand and wrap.

What cellular mechanisms make oligodendrocytes expand, and how can we stimulate these mechanisms to regenerate myelin? In my first aim, I will investigate a pathway called exocytosis, which may be important to add new material to the cell surface. In my second aim, I will develop a method to comprehensively identify unknown pathways required for membrane addition. Towards the first aim, I am using genetic tools in mice to prevent exocytosis specifically in oligodendrocyte during myelin formation. I have already found that genetically preventing exocytosis disrupts myelination, which will allow me to identify which myelin factors are absent and required for myelination. In my second aim, I will purify these oligodendrocytes and use CRISPR genome editing to break genes one-by-one and assess their individual role in allowing the oligodendrocyte to expand. The results from my project will provide new strategies to make oligodendrocytes expand in size and wrap nerve fibers, an essential first step towards rational design of therapies to regenerate lost myelin in disease.