FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells
Year: 2020
Type: article
Abstract: 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.
Source: The Journal of Cell Biology
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: Howard Hughes Medical Institute, March of Dimes Foundation, Brigham and Women's Hospital, National Institutes of Health, University of North Carolina at Chapel Hill, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1111229574, G1226969346, G1703001296, G1762975516, G1880809784, G2081037558, G2347561254, G2460208580, G282708402, G2879526958, G3446040006, G4079461368, ALTERNATIVE SPLICING REGULATION AND MEMBRANE TRAFFICKING, G533176466, Cellular Stress Response Mechanisms, Regulation of Ribosome Biogenesis During Stress, G5916562880, North Carolina Translational and Clinical Science Institute (NC TraCS), G6661309340, G7030279486, G81105876, G853615450, G9000019540, G9000028542, G9000038074, G9000092588, G9000154797, G9000193411, G9000240107, G9000294958, Nutrition Obesity Research Center (NORC), National Xenopus Resource Center, Cancer Center Support Grant
OpenAlex ID: W3010705122