title: Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.
abstract: Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: Louisa K
authors.initials: LK
authors.lastname: Petchey
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Risebro
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, United Kingdom;Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Joaquim M
authors.initials: JM
authors.lastname: Vieira
authors.affiliation: University College London (UCL) Centre for Advanced Biomedical Imaging, London WC1E 6DD, United Kingdom; and.
authors.forename: Tom
authors.initials: T
authors.lastname: Roberts
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: John B
authors.initials: JB
authors.lastname: Bryson
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.affiliation: University College London (UCL) Centre for Advanced Biomedical Imaging, London WC1E 6DD, United Kingdom; and.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, United Kingdom;Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom; paul.riley@dpag.ox.ac.uk.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Riley
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D054792:Muscle, Striated / Q000196:embryology* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014336:Troponin / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; C486442:MLC1A protein, mouse; D018994:Myosin Light Chains; D014336:Troponin; D019210:Troponin I; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C587363:troponin T3, skeletal, fast, mouse