Sox10 and Myrf: Interplay of two transcription factors as cornerstone of the regulatory network in myelinating oligodendrocytes

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Oligodendrocytes are the myelinating cells in the vertebrate central nervous system. They provide nutritional support for axons and allow saltatory conduction. They acquire their ability to myelinate during terminal differentiation as a result of ordered changes of gene expression that are brought about by transcription factors, in particular Sox10 and Myrf. In the last funding period we have shown that Sox10 induces Myrf expression at the onset of terminal differentiation in promyelinating oligodendrocytes by activating an evolutionary conserved Myrf gene enhancer. Both Sox10 and Myrf then synergistically stimulate expression of oligodendroglial differentiation and myelination genes by jointly binding to their regulatory regions. Structure-function studies revealed that Myrf is produced as a trimer that is anchored in the membrane of the endoplasmic reticulum and undergoes autoproteolytic cleavage to liberate an aminoterminal trimer that enters the nucleus and acts as a transcription factor. In preliminary studies we have gained evidence that Myrf not only synergistically stimulates Sox10 function on differentiation genes but also suppresses the expression of genes that Sox10 normally activates in oligodendrocyte precursor cells before differentiation. Myrf may thus be instrumental in allowing Sox10 to switch between target genes. In the current proposal, we will unravel mechanism and physiological importance for the opposite impact of Myrf on both sets of Sox10 target genes by studying DNA binding characteristics and interaction partners of the aminoterminal part of Myrf in close detail. While all Myrf functions have so far been mapped to its aminoterminal region, we have evidence for additional functions of the membrane-bound carboxyterminal part. These will also be investigated on the molecular level.