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Transcriptional regulation of remyelination and its role in axonal health and locomotion

University of British Columbia

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that results in axon loss and disability. Remyelination occurs in MS and can be highly efficient. However in most MS patients, with disease chronicity remyelination fails to regenerate the majority of myelin sheaths around axons leading to chronic demyelination. This is in contrast to rodents, which typically have efficient myelin regeneration and are successful at repairing myelin in most experimental models. Remyelination may be crucial for the preservation of axons following demyelination, but causative experimental evidence demonstrating whether remyelination directly protects axons is currently lacking. I sought to develop a model that mimics remyelination failure in rodents to determine if remyelination is crucial for axonal health and locomotor recovery. In Chapter 2, the transcription factor myelin regulatory factor (MYRF), essential for developmental myelination, was deleted from oligodendrocyte progenitor cells (OPC)s following lysolecithin demyelination. A loss of Myrf in OPCs (Myrf ICKO) resulted in a failure of OPCs to fully differentiate into new oligodendrocytes leaving them vulnerable to apoptosis. New oligodendrocytes could not express myelin proteins and effectively regenerate myelin in Myrf ICKO mice. MS lesions were also examined for the expression of MYRF and Sox10. Fewer MYRF-positive oligodendrocyte lineage cells were found in chronically demyelinated lesions relative to those with remyelination. Therefore, a failure to express MYRF in oligodendrocyte lineage cells is associated with remyelination failure in MS. In Chapter 3, I used the Myrf ICKO mice along with cuprizone/rapamycin demyelination to determine the consequence of remyelination failure on axonal health and locomotor recovery. Inhibited oligodendrogenesis and remyelination following Myrf ICKO aggravated the loss of axons greater than a micron in diameter in the corpus callosum and impaired motor coordination, as assessed on the rotarod, for the first two weeks post cuprizone. However at later time points, Myrf ICKO mice were able to compensate for profound demyelination and improved on the rotarod. Taken together, I demonstrate that oligodendrogenesis and subsequent remyelination requires MYRF, which ameliorates axon loss and improves locomotor recovery. However, over the long-term mice are able to functionally compensate for profound demyelination.

Text

2024-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/65108

Zoology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/