Myrf guides target gene selection of transcription factor Sox10 during oligodendroglial development

Abstract

Oligodendrocytes generate myelin in the vertebrate central nervous system and thus ensure rapid propagation of neuronal activity. Their development is controlled by a network of transcription factors that function as determinants of cell identity or as temporally restricted stage-specific regulators. The continuously expressed Sox10 and Myrf, a factor induced during late development, are particularly important for terminal differentiation. How these factors function together mechanistically and influence each other, is not well understood. Here we show that Myrf not only cooperates with Sox10 during the induction of genes required for differentiation and myelin formation. Myrf also inhibits the activity of Sox10 on genes that are essential during earlier phases of oligodendroglial development. By characterization of the exact DNA-binding requirements of Myrf, we furthermore show that cooperative activation is a consequence of joint binding of Sox10 and Myrf to the same regulatory regions. In contrast, inhibition of Sox10-dependent gene activation occurs on genes that lack Myrf binding sites and likely involves physical interaction between Myrf and Sox10 followed by sequestration. These two opposite activities allow Myrf to redirect Sox10 from genes that it activates in oligodendrocyte precursor cells to genes that need to be induced during terminal differentiation.

Genome‐wide data mining to construct a competing endogenous RNA network and reveal the pivotal therapeutic targets of Parkinson's disease

“…As a member of the HOXB family, HOXB3 was in charge of cell differentiation and proliferation 33 . Besides, MYRF and PLP1 were essential for the oligodendrocytes (OLS) differentiation and myelin maintenance in the central nervous system, which was tightly associated with long‐distance and rapid transmission of nerve electrical impulses 34‐36 . Consistently, we found that the signalling pathways such as myelination and the biosynthesis of differentiation and development of glial cells could promote the pathogenesis of PD.…”

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

“…According to the 'de-repression' model of oligodendrocyte development, differentiation-enhancing transcription factors are initially countered by several negative regulators including ID2, ID4, HES5, SOX5, SOX6 and TCF4 [47][48][49]. Interestingly, reciprocal interactions between NKX2.2, OLIG2 and SOX10 have been described [50], as well as between MYRF and SOX10 [51,52]. Hence, oligodendrocyte development reflects a complex interplay between many spatiotemporally orchestrated signals, rather than a simple positive/negative net sum.…”

The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland

“…In the absence of a good correlation between effector and target gene expression, we postulate that the interaction with temporally and spatially restricted transcription factors is a major determinant of Sox10 function during involution. The relevance of such interactions for stage-specific Sox10 functions has been documented in other cell types such as oligodendroglia 33 , 34 . Previous studies had shown that miR-424 and miR-503 function downstream of TGF-β during involution 20 .…”