Dataset Information

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.

SUBMITTER: Aprato J

PROVIDER: S-EPMC7026603 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Aprato Jessica J Sock Elisabeth E Weider Matthias M Elsesser Olga O Fröb Franziska F Wegner Michael M

Nucleic acids research 20200201 3

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 ...[more]

PMID: 31828317

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Project description:Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC.

Dataset Information

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

Publications

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

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