Fragile-X mental retardation autosomal homologue-1 (FXR1) is a muscle-enriched RNA-binding protein. FXR1 depletion is perinatally lethal in mice, Xenopus, and zebrafish; however, the mechanisms driving these phenotypes remain unclear. The FXR1 gene undergoes alternative splicing, producing multiple protein isoforms and mis-splicing has been implicated in disease. Furthermore, mutations that cause frameshifts in muscle-specific isoforms result in congenital multi-minicore myopathy. We observed that FXR1 alternative splicing is pronounced in the serine- and arginine-rich intrinsically disordered domain; these domains are known to promote biomolecular condensation. Here, we show that tissue-specific splicing of fxr1 is required for Xenopus development and alters the disordered domain of FXR1. FXR1 isoforms vary in the formation of RNA-dependent biomolecular condensates in cells and in vitro. This work shows that regulation of tissue-specific splicing can influence FXR1 condensates in muscle development and how mis-splicing promotes disease.
FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells
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Jean A. Smith, Ennessa G. Curry, R. Eric Blue, Christine Roden, Samantha E.R. Dundon, Anthony Rodríguez-Vargas, Danielle C. Jordan, Xiaomin Chen, Shawn M. Lyons, John Crutchley, Paul Anderson, Marko E. Horb, Amy S. Gladfelter, Jimena Giudice; FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells. J Cell Biol 6 April 2020; 219 (4): e201911129. doi: https://doi.org/10.1083/jcb.201911129
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