Giudice Jimena

Giudice

Jimena

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FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells

(Rockefeller University Press, 2020-03-13) Smith, Jean A. ; Curry, Ennessa G. ; Blue, R. Eric ; Roden, Christine ; Dundon, Samantha E.R. ; Rodríguez-Vargas, Anthony ; Jordan, Danielle C. ; Chen, Xiaomin ; Lyons, Shawn M. ; Crutchley, John M. ; Anderson, Paul ; Horb, Marko E. ; Gladfelter, Amy S. ; Giudice, Jimena

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.