Risebro Catherine A, Searles Richelle G, Melville Athalie A D, Ehler Elisabeth, Jina Nipurna, Shah Sonia, Pallas Jacky, Hubank Mike, Dillard Miriam, Harvey Natasha L, Schwartz Robert J, Chien Kenneth R, Oliver Guillermo, Riley Paul R
Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
Development. 2009 Feb;136(3):495-505. doi: 10.1242/dev.030007. Epub 2008 Dec 17.
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.
心肌生长受损和心肌细胞排列异常是先天性心脏病和心肌病的基础。我们发现，小鼠同源盒转录因子Prox1在心脏中的特异性失活会导致肌节蛋白的表达和定位紊乱、粗大肌原纤维排列紊乱以及心脏生长迟缓。此外，我们证明Prox1是编码结构蛋白α-辅肌动蛋白、N-RAP和斑联蛋白的基因直接转录调控所必需的，这些蛋白共同作用以维持肌动蛋白-α-辅肌动蛋白的相互作用，这是肌节的基本关联。心脏发育异常和一部分肌肉疾病的表现以前被归因于关键结构蛋白的突变。我们的研究揭示了在促进胎儿心肌细胞肥大、维持收缩功能以及向遗传性或获得性肌病发展的背景下，对肌节完整性进行直接转录调控的基本要求。
