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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.

Original publication

DOI

10.1073/pnas.1406191111

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

01/07/2014

Volume

111

Pages

9515 - 9520

Keywords

Animals, Cardiomyopathy, Dilated, Cell Differentiation, Chromatin Immunoprecipitation, DNA Primers, Fluorescent Antibody Technique, Gene Expression Regulation, Developmental, Homeodomain Proteins, Mice, Mice, Knockout, Microarray Analysis, Muscle, Striated, Myocardium, Myosin Light Chains, Real-Time Polymerase Chain Reaction, Troponin, Troponin I, Tumor Suppressor Proteins