Transcriptional control of myelin maintenance in the adult CNS

© 2015 Dr. Matthias KoenningOligodendrocyte differentiation and the myelination of axons are crucial aspects of vertebrate central nervous system development and function. The processes of oligodendrocyte differentiation and the expression of these myelin proteins are tightly controlled by a number of transcription factors. Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Myelin Regulatory Factor (MyRF), a putative transcription factor, is critical for the generation of mature oligodendrocytes and the initiation of myelination during development. It has however not been investigated whether MyRF is also required for the ongoing maintenance of myelin once oligodendrocyte differentiation is complete. Moreover, whether it is really a transcription factor has also been unclear, given it contains a putative transmembrane domain and the ability of the MyRF protein to interact with DNA has not been demonstrated. The aims of this thesis were therefore to investigate the roles of MyRF in the mature CNS, and to determine the molecular mechanisms by which it promotes myelination. To investigate whether ongoing expression of MyRF is required to maintain a mature myelinated central nervous system, an inducible conditional knockout strategy was used to ablate MyRF specifically in mature oligodendrocytes of adult mice. This approach resulted in a rapid down-regulation of key myelin genes, followed by an eventual death of many of the recombined oligodendrocytes and a delayed, but severe, CNS demyelination. As such, MyRF has clear roles in regulating myelination beyond the initial phase of oligodendrocyte differentiation. At the molecular level, it was found that MyRF is a novel example of a membrane-tethered transcription factor which undergoes cleavage via a unique autoproteolytic mechanism previously undescribed in eukaryotic cells. This mechanism relies on a protein domain previously only reported in bacteriophage tailspike proteins. This cleavage of MyRF allows the N-terminal cleavage product to translocate to the nucleus, where it directly binds DNA via evolutionary conserved residues and directly promotes expression of myelin genes. Together, these data provide crucial insights into the biological roles of MyRF, establishing it as a novel type of transcription factor with a direct role in regulating the expression of genes required for myelination in both the developing and mature CNS