title: The myogenic repressor gene Holes in muscles is a direct transcriptional target of Twist and Tinman in the Drosophila embryonic mesoderm.
abstract: Understanding the regulatory circuitry controlling myogenesis is critical to understanding developmental mechanisms and developmentally-derived diseases. We analyzed the transcriptional regulation of a Drosophila myogenic repressor gene, Holes in muscles (Him). Previously, Him was shown to inhibit Myocyte enhancer factor-2 (MEF2) activity, and is expressed in myoblasts but not differentiating myotubes. We demonstrate that different phases of Him embryonic expression arises through the actions of different enhancers, and we characterize the enhancer required for its early mesoderm expression. This Him early mesoderm enhancer contains two conserved binding sites for the basic helix-loop-helix regulator Twist, and one binding site for the NK homeodomain protein Tinman. The sites for both proteins are required for enhancer activity in early embryos. Twist and Tinman activate the enhancer in tissue culture assays, and ectopic expression of either factor is sufficient to direct ectopic expression of a Him-lacZ reporter, or of the endogenous Him gene. Moreover, sustained expression of twist in the mesoderm up-regulates mesodermal Him expression in late embryos. Our findings provide a model to define mechanistically how Twist can both promotes myogenesis through direct activation of Mef2, and can place a brake on myogenesis, through direct activation of Him.
authors.affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Elwell
authors.affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: TyAnna L
authors.initials: TL
authors.lastname: Lovato
authors.affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Adams
authors.affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Baca
authors.affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Thai
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Biology, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: rcripps@unm.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cripps
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004330:Drosophila / Q000145:classification / Q000235:genetics; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000378:metabolism; D008969:Molecular Sequence Data; D024510:Muscle Development; D032383:Myocytes, Cardiac / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C524674:Him protein, Drosophila; C499409:Mef2 protein, Drosophila; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D015534:Trans-Activators; C497753:Twi protein, Drosophila; D051879:Twist-Related Protein 1; C102933:tin protein, Drosophila
keywords: Drosophila; MEF2; Mesoderm; Myocyte enhancer factor-2; Myogenesis; Regulatory network; Tinman; Transcriptional regulation; Twist