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: 6.27). 01/2009; 136(3):495-505. DOI: 10.1242/dev.030007
Source: PubMed

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.

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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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    ABSTRACT: Anisotropies that underlie organ morphogenesis have been quantified in 2D, taking advantage of a reference axis. However, morphogenesis is a 3D process and it remains a challenge to analyze cell polarities in 3D. Here, we have designed a novel procedure that integrates multidisciplinary tools, including image segmentation, statistical analyses, axial clustering and correlation analysis. The result is a sensitive and unbiased assessment of the significant alignment of cell orientations in 3D, compared with a random axial distribution. Taking the mouse heart as a model, we validate the procedure at the fetal stage, when cardiomyocytes are known to be aligned. At the embryonic stage, our study reveals that ventricular cells are already coordinated locally. The centrosome-nucleus axes and the cell division axes are biased in a plane parallel to the outer surface of the heart, with a minor transmural component. We show further alignment of these axes locally in the plane of the heart surface. Our method is generally applicable to other sets of vectors or axes in 3D tissues to map the regions where they show significant alignment.
    Development 01/2013; 140(2):395-404. DOI:10.1242/dev.087940 · 6.27 Impact Factor
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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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    ABSTRACT: Epidemiological studies have correlated arsenic exposure in drinking water with adverse developmental outcomes such as stillbirths, spontaneous abortions, neonatal mortality, low birth weight, delays in the use of musculature, and altered locomotor activity. Killifish (Fundulus heteroclitus) were used as a model to help to determine the mechanisms by which arsenic could impact development. Killifish embryos were exposed to three different sodium arsenite concentrations and were collected at 32 h post-fertilization (hpf), 42 hpf, 168 hpf, or < 24 h post-hatch. A killifish oligo microarray was developed and used to examine gene expression changes between control and 25-ppm arsenic-exposed hatchlings. With artificial neural network analysis of the transcriptomic data, accurate prediction of each group (control vs. arsenic-exposed embryos) was obtained using a small subset of only 332 genes. The genes differentially expressed include those involved in cell cycle, development, ubiquitination, and the musculature. Several of the genes involved in cell cycle regulation and muscle formation, such as fetuin B, cyclin D-binding protein 1, and CapZ, were differentially expressed in the embryos in a time- and dose-dependent manner. Examining muscle structure in the hatchlings showed that arsenic exposure during embryogenesis significantly reduces the average muscle fiber size, which is coupled with a significant 2.1- and 1.6-fold upregulation of skeletal myosin light and heavy chains, respectively. These findings collectively indicate that arsenic exposure during embryogenesis can initiate molecular changes that appear to lead to aberrant muscle formation.
    Toxicological Sciences 11/2011; 125(2):522-31. DOI:10.1093/toxsci/kfr302 · 4.48 Impact Factor
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    • "Consistent with this model, N- RAP knockdown by RNA interference in mouse cardiomyocytes demonstrated that α-actinin organization into myofibrils is closely linked to N-RAP levels (Dhume et al. 2006). Interestingly, N-RAP and α-actinin levels are both regulated by the transcription factor Prox1, and a cardiac-specific knockout of Prox1 leads to disorganization of sarcomeric proteins (Risebro et al. 2009). "
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    ABSTRACT: Sarcomere assembly in striated muscles has long been described as a series of steps leading to assembly of individual proteins into thick filaments, thin filaments and Z-lines. Decades of previous work focused on the order in which various structural proteins adopted the striated organization typical of mature myofibrils. These studies led to the view that actin and α-actinin assemble into premyofibril structures separately from myosin filaments, and that these structures are then assembled into myofibrils with centered myosin filaments and actin filaments anchored at the Z-lines. More recent studies have shown that particular scaffolding proteins and chaperone proteins are required for individual steps in assembly. Here, we review the evidence that N-RAP, a LIM domain and nebulin repeat protein, scaffolds assembly of actin and α-actinin into I-Z-I structures in the first steps of assembly; that the heat shock chaperone proteins Hsp90 & Hsc70 cooperate with UNC-45 to direct the folding of muscle myosin and its assembly into thick filaments; and that the kelch repeat protein Krp1 promotes lateral fusion of premyofibril structures to form mature striated myofibrils. The evidence shows that myofibril assembly is a complex process that requires the action of particular catalysts and scaffolds at individual steps. The scaffolds and chaperones required for assembly are potential regulators of myofibrillogenesis, and abnormal function of these proteins caused by mutation or pathological processes could in principle contribute to diseases of cardiac and skeletal muscles.
    Biophysical Reviews 03/2011; 3(1):25-32. DOI:10.1007/s12551-011-0043-x
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