title: Redox regulation by Pitx2 and Pitx3 is critical for fetal myogenesis.
abstract: During development, major metabolic changes occur as cells become more specialized within a lineage. In the case of skeletal muscle, differentiation is accompanied by a switch from a glycolytic proliferative progenitor state to an oxidative postmitotic differentiated state. Such changes require extensive mitochondrial biogenesis leading to increased reactive oxygen species (ROS) production that needs to be balanced by an antioxidant system. Our analysis of double conditional Pitx2/3 mouse mutants, both in vivo during fetal myogenesis and ex vivo in primary muscle cell cultures, reveals excessive upregulation of ROS levels leading to DNA damage and apoptosis of differentiating cells. This is a consequence of downregulation of Nrf1 and genes for antioxidant enzymes, direct targets of Pitx2/3, leading to decreased expression of antioxidant enzymes, as well as impairment of mitochondrial function. Our analysis identifies Pitx2 and Pitx3 as key regulators of the intracellular redox state preventing DNA damage as cells undergo differentiation.
authors.affiliation: Department of Developmental and Stem Cell Biology, CNRS URA 2578, 28 rue du Dr Roux, 75015 Paris, France. Electronic address: aurore.lhonore@pasteur.fr.
authors.forename: Aurore
authors.initials: A
authors.lastname: L'honoré
authors.affiliation: Platform of Cytometry, Institut Pasteur, 28 rue du Dr Roux, 75015 Paris, France.
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Commère
authors.affiliation: Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Ouimette
authors.affiliation: Department of Developmental and Stem Cell Biology, CNRS URA 2578, 28 rue du Dr Roux, 75015 Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Montarras
authors.affiliation: Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Drouin
authors.affiliation: Department of Developmental and Stem Cell Biology, CNRS URA 2578, 28 rue du Dr Roux, 75015 Paris, France.
authors.forename: Margaret
authors.initials: M
authors.lastname: Buckingham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development; D009154:Mutation; D051266:Nuclear Respiratory Factor 1 / Q000096:biosynthesis / Q000235:genetics*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D051266:Nuclear Respiratory Factor 1; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C495634:Nrf1 protein, mouse; C433629:homeobox protein PITX3