Abstract
Author SummaryOligodendrocytes are a highly specialized cell type that surround axons of the vertebrate central nervous system with myelin, electrically insulating them and allowing rapid and energy-efficient propagation of nerve signals. We previously identified a protein, MYRF, that is required for the final stages of oligodendrocyte differentiation and myelination. Although we proposed that MYRF might act as a transcription factor, it remains uncertain whether this is true, given that MYRF and related proteins contain a transmembrane domain that might preclude localization to the nucleus. Here, we show that the MYRF protein undergoes an activating cleavage event to release the functional transcription factor from the transmembrane domain that otherwise anchors it to the endoplasmic reticulum. Unexpectedly, this cleavage event is mediated by a portion of MYRF that is related to a self-cleaving domain found in bacteriophage proteins. This distinguishes it from other membrane-associated transcription factors that are cleaved via regulated proteolysis within the membrane bilayer. We find that the N-terminal product of MYRF cleavage directly binds to a wide range of genes involved in myelination, stimulating their expression. Many of these MYRF binding sites identify previously uncharacterized enhancers for these myelin genes.
Highlights
Oligodendrocytes are the myelinating cells of the vertebrate central nervous system (CNS); their development and the ensheathment of receptive neuronal axons are vital for the rapid propagation of nerve impulses
We previously identified a protein, myelin regulatory factor (MYRF), that is required for the final stages of oligodendrocyte differentiation and myelination
We proposed that MYRF might act as a transcription factor, it remains uncertain whether this is true, given that MYRF and related proteins contain a transmembrane domain that might preclude localization to the nucleus
Summary
Oligodendrocytes are the myelinating cells of the vertebrate CNS; their development and the ensheathment of receptive neuronal axons are vital for the rapid propagation of nerve impulses. The differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and their subsequent myelination of axons are highly regulated processes. The factors involved in the development of the oligodendrocyte lineage have been relatively well characterized. The transcription factor Olig is required for specification of OPCs from subventricular zone precursor cells, at least within ventral regions of the CNS [1,2]. A number of other transcription factors are subsequently required for the successful differentiation of OPCs into myelinating oligodendrocytes including Olig1 [4], Nkx2.2 [5], Ascl1/Mash1 [6], Zfp191 [7], and Sox10 [8,9]
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