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Regulation of FXR1 by alternative splicing is required for muscle development and controls liquid-like condensates in muscle cells

Authors: 
Smith JA, Curry EG, Blue RE, Roden C, Dundon SER, Rodríguez-Vargas A, Jordan DC, Chen X, Lyons SW, Crutchley J, Anderson P, Horb ME, Gladfelter AS, Giudice J
Citation: 
bioRxiv. 2019;[preprint] doi:10.1101/818476
Abstract: 
Fragile-X mental retardation autosomal homolog-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. bioRxiv. 2019;[preprint] doi:10.1101/818476
Epub: 
Not Epub
Organism or Cell Type: 
Xenopus tropicalis
Delivery Method: 
microinjection