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.
The cell biology field has outstanding working knowledge of the fundamentals of membrane-trafficking pathways, which are of critical importance in health and disease. Current challenges include understanding how trafficking pathways are fine-tuned for specialized tissue functions and during development. In parallel, the ENCODE project and numerous genetic studies have revealed that alternative splicing regulates gene expression in tissues and throughout development at a post-transcriptional level. This Review summarizes recent discoveries demonstrating that alternative splicing affects tissue specialization and membrane-trafficking proteins during development, and examines how this regulation is altered in human disease. We first discuss how alternative splicing of clathrin, SNAREs and BAR-domain proteins influences endocytosis, secretion and membrane dynamics, respectively. We then focus on the role of RNA-binding proteins in the regulation of splicing of membrane-trafficking proteins in health and disease. Overall, our aim is to comprehensively summarize how trafficking is molecularly influenced by alternative splicing and identify future directions centered on its physiological relevance.
intestinal stem cells Progenitor EECsMature EECs miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling.CONCLUSIONS: This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling. (Cell Mol Gastroenterol Hepatol 2020;9:447-464; https://doi.
The role of individual miRNAs in small intestinal (SI) epithelial homeostasis is under-explored. In this study, we discovered that miR-375 is among the most enriched miRNAs in intestinal crypts and stem cells (ISCs), especially facultative ISCs. We then showed by multiple manipulations, including CRISPR/Cas9 editing, that miR-375 is strongly suppressed by Wnt-signaling. Single-cell RNA-seq analysis of SI crypt-enriched cells from miR-375 knockout (375-KO) mice revealed elevated numbers of tuft cells and increased expression of pro-proliferative genes in ISCs. Accordingly, the genetic loss of miR-375 promoted resistance to helminth infection and enhanced the regenerative response to irradiation. The conserved effects of miR-375 were confirmed by gain-of-function studies in Drosophila midgut stem cells in vivo. Moreover, functional experiments in enteroids uncovered a regulatory relationship between miR-375 and Yap1 that controls cell survival. Finally, analysis of mouse model and clinical data revealed an inverse association between miR-375 levels and intestinal tumor development.
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 missplicing 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 intrinsicallydisordered 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 RNAdependent 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. KEYWORDS FXR1, alternative splicing, biomolecular condensation, myogenesis, Xenopus, muscle HIGHLIGHTS • The muscle-specific exon 15 impacts FXR1 functions • Alternative splicing of FXR1 is tissue-and developmental stage specific • FXR1 forms RNA-dependent condensates • Splicing regulation changes FXR1 condensate properties
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