Abstract
The genetic lesion that is diagnostic for facioscapulohumeral muscular dystrophy (FSHD) results in an epigenetic misregulation of gene expression, which ultimately leads to the disease pathology. FRG1 (FSHD region gene 1) is a leading candidate for a gene whose misexpression might lead to FSHD. Because FSHD pathology is most prominent in the musculature, most research and therapy efforts focus on muscle cells. Previously, using Xenopus development as a model, we showed that altering frg1 expression levels systemically leads to aberrant muscle development, illustrating the potential for aberrant FRG1 levels to disrupt the musculature. However, 50-75% of FSHD patients also exhibit retinal vasculopathy and FSHD muscles have increased levels of vascular- and endothelial-related FRG1 transcripts, illustrating an underlying vascular component to the disease. To date, no FSHD candidate gene has been proposed to affect the vasculature. Here, we focus on a role for FRG1 expression in the vasculature. We found that endogenous frg1 is expressed in both the developing and adult vasculature in Xenopus. Furthermore, expression of FRG1 was found to be essential for the development of the vasculature, as a knockdown of FRG1 resulted in decreased angiogenesis and reduced expression of the angiogenic regulator DAB2. Conversely, tadpoles subjected to frg1 overexpression displayed the pro-angiogenic phenotypes of increased blood vessel branching and dilation of blood vessels, and developed edemas, suggesting that their circulation was disrupted. Thus, the systemic upregulation of the FRG1 protein shows the potential for acquiring a disrupted vascular phenotype, providing the first link between a FSHD candidate gene and the vascular component of FSHD pathology. Overall, in conjunction with our previous analysis, we show that FRG1 overexpression is capable of disrupting both the musculature and vasculature, recapitulating the two most prominent features of FSHD.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy characterized by progressive atrophy of the facial, shoulder and upper arm muscles
FRG1 is expressed in vascular tissues Two of the prominent pathological effects in FSHD patients are the progressive appearance of dystrophic skeletal muscle and retinal vasculopathy
Either sagitally or transversely, and immunostained for FRG1 (Fig. 1A) show significant FRG1 expression within the pronephrous (Fig. 1B,C), posterior cardinal vein and arteries (Fig. 1C), indicating that FRG1 is expressed in the vasculature
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy characterized by progressive atrophy of the facial, shoulder and upper arm muscles. The FSHD genetic lesion is a contraction of the tandem array of 3.3 kb D4Z4 repeats at chromosome 4q35 to below a threshold of 11 copies (Lunt et al, 1995; Wijmenga et al, 1992). This repeat contraction is hypothesized to affect the expression of neighboring gene(s). Measurements of FRG1 mRNA levels from the muscles of FSHD patients have varied, including a 25-fold increase in expression, unchanged expression and a 5-fold decrease in expression, when compared with control muscles (van Deutekom et al, 1996; Gabellini et al, 2002; Jiang et al, 2003; Winokur et al, 2003; Osborne et al, 2007). A correlation between FRG1 mRNA levels in skeletal muscle and FSHD pathology remains inconclusive and controversial
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