title: MicroRNA-30a regulates zebrafish myogenesis through targeting the transcription factor Six1.
abstract: Precise spatiotemporal regulation of the SIX1 homeoprotein is required to coordinate vital tissue development, including myogenesis. Whereas SIX1 is downregulated in most tissues following embryogenesis, it is re-expressed in numerous cancers, including tumors derived from muscle progenitors. Despite crucial roles in development and disease, the upstream regulation of SIX1 expression has remained elusive. Here, we identify the first direct mechanism for Six1 regulation in embryogenesis, through microRNA30a (miR30a)-mediated repression. In zebrafish somites, we show that miR30a and six1a and six1b (hereafter six1a/b) are expressed in an inverse temporal pattern. Overexpression of miR30a leads to a reduction in six1a/b levels, and results in increased apoptosis and altered somite morphology, which phenocopies six1a/b knockdown. Conversely, miR30a inhibition leads to increased Six1 expression and abnormal somite morphology, revealing a role for endogenous miR30a as a muscle-specific miRNA (myomiR). Importantly, restoration of six1a in miR30a-overexpressing embryos restores proper myogenesis. These data demonstrate a new role for miR30a at a key node in the myogenic regulatory gene network through controlling Six1 expression.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Jenean H
authors.initials: JH
authors.lastname: O'Brien
authors.affiliation: Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hernandez-Lagunas
authors.affiliation: Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA Kristin.Artinger@ucdenver.edu Heide.Ford@ucdenver.edu.
authors.forename: Kristin Bruk
authors.initials: KB
authors.lastname: Artinger
authors.affiliation: Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA Kristin.Artinger@ucdenver.edu Heide.Ford@ucdenver.edu.
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D024510:Muscle Development / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C585572:MIRN30 microRNA, zebrafish; D035683:MicroRNAs; C498351:Six1 protein, zebrafish; D029961:Zebrafish Proteins
keywords: Myogenesis; Six1; Zebrafish; microRNA-30a