April 21, 2009
FSH Society initiated research and fellowship leads to publication of paper in Disease Models and Mechanisms – showing FRG1 gene is expressed in
vascular structures, may be involved in retinal problems in FSHD, and is essential for angiogenesis. Research was suported by a FSH Society Landsman Charitable Trust Fellowship #FSHS-LCT-001 awarded to Meredith Hanel
Dis Model Mech. 2009 May-Jun;2(5-6):267-74. Epub 2009 Apr 21.
FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy.
Wuebbles RD, Hanel ML, Jones PL.
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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.
PMID: 19383939 [PubMed - in process]
[Excerpt from paper]
ACKNOWLEDGEMENTS
We thank Jon Henry and Phil Newmark, UIUC, for technical support. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant #1RO1AR055877 awarded to P.L.J. and the FSH Society Landsman Charitable Trust Fellowship #FSHS-LCT-001 awarded to M.L.H.
