title: Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs.
abstract: During development of myelin-forming oligodendrocytes in the central nervous system the two closely related transcription factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct transcriptional targets of Sox10. The two microRNAs in turn recognize the 3'-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels posttranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Reiprich
authors.affiliation: Department of Dermatology, Laboratory of Systems Tumor Immunology, Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Cantone
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Weider
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Baroti
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Wittstatt
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Küspert
authors.affiliation: Department of Dermatology, Laboratory of Systems Tumor Immunology, Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Julio
authors.initials: J
authors.lastname: Vera
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-4586-3294
authors.initials: M
authors.lastname: Wegner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008962:Models, Theoretical; D004676:Myelin Basic Protein / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2 / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D051381:Rats; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D005904:Glial Fibrillary Acidic Protein; C436006:Mbp protein, rat; D008565:Membrane Proteins; D035683:MicroRNAs; D004676:Myelin Basic Protein; C409875:Myrf protein, human; D000076104:Oligodendrocyte Transcription Factor 2; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055757:SOXE Transcription Factors; C527925:Sox10 protein, rat; D014157:Transcription Factors; D049452:Green Fluorescent Proteins
keywords: HMG; Sox; glia; miR338; oligodendrocyte