Faculty Collaboration Database

The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function. Hum Mol Genet 2015 Apr 15;24(8):2360-74

Date

01/13/2015

Pubmed ID

25575511

Pubmed Central ID

PMC4380076

DOI

10.1093/hmg/ddv003

Scopus ID

2-s2.0-84926480647 (requires institutional sign-in at Scopus site)   53 Citations

Abstract

The Rbfox family of RNA-binding proteins is highly conserved with established roles in alternative splicing (AS) regulation. High-throughput studies aimed at understanding transcriptome remodeling have revealed skeletal muscle as displaying one of the largest number of AS events. This finding is consistent with requirements for tissue-specific protein isoforms needed to sustain muscle-specific functions. Rbfox1 is abundant in vertebrate brain, heart and skeletal muscle. Genome-wide genetic approaches have linked the Rbfox1 gene to autism, and a brain-specific knockout mouse revealed a critical role for this splicing regulator in neuronal function. Moreover, a Caenorhabditis elegans Rbfox1 homolog regulates muscle-specific splicing. To determine the role of Rbfox1 in muscle function, we developed a conditional knockout mouse model to specifically delete Rbfox1 in adult tissue. We show that Rbfox1 is required for muscle function but a >70% loss of Rbfox1 in satellite cells does not disrupt muscle regeneration. Deep sequencing identified aberrant splicing of multiple genes including those encoding myofibrillar and cytoskeletal proteins, and proteins that regulate calcium handling. Ultrastructure analysis of Rbfox1(-/-) muscle by electron microscopy revealed abundant tubular aggregates. Immunostaining showed mislocalization of the sarcoplasmic reticulum proteins Serca1 and Ryr1 in a pattern indicative of colocalization with the tubular aggregates. Consistent with mislocalization of Serca1 and Ryr1, calcium handling was drastically altered in Rbfox1(-/-) muscle. Moreover, muscle function was significantly impaired in Rbfox1(-/-) muscle as indicated by decreased force generation. These results demonstrate that Rbfox1 regulates a network of AS events required to maintain multiple aspects of muscle physiology.

Author List

Pedrotti S, Giudice J, Dagnino-Acosta A, Knoblauch M, Singh RK, Hanna A, Mo Q, Hicks J, Hamilton S, Cooper TA

MESH terms used to index this publication - Major topics in bold

Alternative Splicing
Animals
Calcium
Female
Humans
Male
Mice
Mice, Knockout
Muscle, Skeletal
Muscular Diseases
Myoblasts
RNA Splicing Factors
RNA-Binding Proteins
Satellite Cells, Skeletal Muscle