Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions

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Abstract

Postnatal development of skeletal muscle is a highly dynamic period of tissue remodeling. Here, we used RNA-seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrate that alternative splicing developmental transitions impact muscle physiology. The first 2 weeks after birth are particularly dynamic for differential gene expression and alternative splicing transitions, and calcium-handling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of the three calcineurin A genes, calcium-dependent phosphatases that regulate multiple aspects of muscle biology. Redirected splicing of calcineurin A to the fetal isoforms in adult muscle and in differentiated C2C12 slows the timing of muscle relaxation, promotes nuclear localization of calcineurin target Nfatc3, and/or affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of alternative splicing during muscle postnatal development.

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The evolutionary landscape of alternative splicing in vertebrate species.

Nuno L Barbosa-Morais, Manuel Irimia, Qun Pan … (2012)

How species with similar repertoires of protein-coding genes differ so markedly at the phenotypic level is poorly understood. By comparing organ transcriptomes from vertebrate species spanning ~350 million years of evolution, we observed significant differences in alternative splicing complexity between vertebrate lineages, with the highest complexity in primates. Within 6 million years, the splicing profiles of physiologically equivalent organs diverged such that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are cis-directed. However, a subset of pronounced splicing changes are predicted to remodel protein interactions involving trans-acting regulators. These events likely further contributed to the diversification of splicing and other transcriptomic changes that underlie phenotypic differences among vertebrate species.

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Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage.

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Following their discovery in 1961, it was speculated that satellite cells were dormant myoblasts, held in reserve until required for skeletal muscle repair. Evidence for this accumulated over the years, until the link between satellite cells and the myoblasts that appear during muscle regeneration was finally established. Subsequently, it was demonstrated that, when grafted, satellite cells could also self-renew, conferring on them the coveted status of 'stem cell'. The emergence of other cell types with myogenic potential, however, questioned the precise role of satellite cells. Here, we review recent recombination-based studies that have furthered our understanding of satellite cell biology. The clear consensus is that skeletal muscle does not regenerate without satellite cells, confirming their pivotal and non-redundant role.

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A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart.

Auinash Kalsotra, Xinshu Xiao, Amanda J Ward … (2009)

From a large-scale screen using splicing microarrays and RT-PCR, we identified 63 alternative splicing (AS) events that are coordinated in 3 distinct temporal patterns during mouse heart development. More than half of these splicing transitions are evolutionarily conserved between mouse and chicken. Computational analysis of the introns flanking these splicing events identified enriched and conserved motifs including binding sites for CUGBP and ETR-3-like factors (CELF), muscleblind-like (MBNL) and Fox proteins. We show that CELF proteins are down-regulated >10-fold during heart development, and MBNL1 protein is concomitantly up-regulated nearly 4-fold. Using transgenic and knockout mice, we show that reproducing the embryonic expression patterns for CUGBP1 and MBNL1 in adult heart induces the embryonic splicing patterns for more than half of the developmentally regulated AS transitions. These findings indicate that CELF and MBNL proteins are determinative for a large subset of splicing transitions that occur during postnatal heart development.

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Author and article information

Contributors

James Anthony Loehr

Wei Li

George Gerald Rodney

Thomas A Cooper:

ORCID: http://orcid.org/0000-0002-9238-0578

Benjamin J Blencowe: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 11 August 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e27192

Affiliations

[1 ]deptDepartment of Molecular and Cellular Biology Baylor College of Medicine HoustonUnited States

[2 ]deptDepartment of Pathology and Immunology Baylor College of Medicine HoustonUnited States

[3 ]deptDivision of Biostatistics, Dan L Duncan Cancer Center Baylor College of Medicine HoustonUnited States

[4 ]deptDepartment of Molecular Physiology and Biophysics Baylor College of Medicine HoustonUnited States

University of Toronto Canada

Author notes

[†]

Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, United States.

Author information

Thomas A Cooper http://orcid.org/0000-0002-9238-0578

Article

Publisher ID: 27192

DOI: 10.7554/eLife.27192

PMC ID: 5577920

PubMed ID: 28826478

SO-VID: 7081b86f-6efc-4c94-a74d-44096b44e4ea

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.