title: Prox1 maintains muscle structure and growth in the developing heart.
abstract: Impaired cardiac muscle growth and aberrant myocyte arrangement underlie congenital heart disease and cardiomyopathy. We show that cardiac-specific inactivation of the murine homeobox transcription factor Prox1 results in the disruption of expression and localisation of sarcomeric proteins, gross myofibril disarray and growth-retarded hearts. Furthermore, we demonstrate that Prox1 is required for direct transcriptional regulation of the genes encoding the structural proteins alpha-actinin, N-RAP and zyxin, which collectively function to maintain an actin-alpha-actinin interaction as the fundamental association of the sarcomere. Aspects of abnormal heart development and the manifestation of a subset of muscular-based disease have previously been attributed to mutations in key structural proteins. Our study reveals an essential requirement for direct transcriptional regulation of sarcomere integrity, in the context of enabling foetal cardiomyocyte hypertrophy, maintenance of contractile function and progression towards inherited or acquired myopathic disease.
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Risebro
authors.forename: Richelle G
authors.initials: RG
authors.lastname: Searles
authors.forename: Athalie A D
authors.initials: AA
authors.lastname: Melville
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ehler
authors.forename: Nipurna
authors.initials: N
authors.lastname: Jina
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Jacky
authors.initials: J
authors.lastname: Pallas
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.forename: Miriam
authors.initials: M
authors.lastname: Dillard
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Guillermo
authors.initials: G
authors.lastname: Oliver
authors.forename: Paul R
authors.initials: PR
authors.lastname: Riley
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008667:Metalloproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D012518:Sarcomeres / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D060589:Zyxin; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D008667:Metalloproteins; D009124:Muscle Proteins; C491567:Nrap protein, mouse; D025521:Tumor Suppressor Proteins; C498285:Zyx protein, mouse; D060589:Zyxin; D000098551:Prospero-Related Homeobox 1 Protein; D000185:Actinin