Prox1 maintains muscle structure and growth in the developing heart

Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
Development (Impact Factor: 6.46). 01/2009; 136(3):495-505. DOI: 10.1242/dev.030007
Source: PubMed


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.

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    • "Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field [44]; it also controls regional coronary artery morphogenesis [45], aorta morphogenesis [46], and blood vessel development [47]. Prox1 is known to function as a direct upstream modifier of Nkx2.5 and is responsible for maintaining muscle structure and growth [48, 49]. CAMTAs promote cardiomyocyte hypertrophy and activate the ANF gene, at least in part, by associating with the cardiac homeodomain protein Nkx2-5 [50]. "
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    • "Whereas the architecture of the fetal myocardium was reported to be anisotropic, this is not the case for the embryonic heart, based on cell elongation and sarcomere orientation (Risebro et al., 2009). "
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    • "Modules 11 and 12 contain a number of genes associated with immune response, energy metabolism, and along with module 13, contain genes needed for cellular development and differentiation (b-catenin, BMP1b, and transmembrane 4l six family member 5). Module 14 contains the Prox1 gene, which is required for transcriptional regulation of alpha-actinin, nebulin-related anchoring protein, and zyxin, which function to maintain the actin-alpha-actinin association of the sarcomere (Risebro et al., 2009). Module 15 from the MMC indicated that genes involved in the musculature, such as troponin C2, ataxin 2, glycogen synthase kinase 3b, and CapZ were altered. "
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