Diversification of the muscle proteome through alternative splicing

Figures

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  Fig. 1. Mechanism and mode of pre-mRNA splicing. a The U1 snRNP particle recognizes the 5′ splice site while U2 recognizes the adenosine (A) of the branch point. Subsequently to the entry of the heterotrimeric (pre-assembled) U4/U6-U5 particle, several rearrangements lead to the catalytic activation of the spliceosome. This results in the displacement of U4 and U1 snRNPs with a concomitant attack of the 2′ OH of the adenosine of the branch site to the 5′ splice site generating a lariat intron-3′ exon intermediate. Finally, the 3′ OH of the free 5′ exon attacks the 3′ splice site, thus releasing the lariat intron and ligating the two exons. b Modes of alternative splicing reactions. Alternatively, spliced mRNAs are generated through inclusion (or skipping) of cassette exons, mutually exclusive exons, usage of 5′ and 3′ splice sites, intron retention, alternative promoters, or polyadenylation sites

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  Fig. 2. Cis-elements and trans-acting factors regulate pre-mRNA splicing during myogenesis. a Pre-mRNA harboring various cis-acting regulatory sequences able to promote (+) or inhibit (−) recognition of alternative splicing exons. Based on their position, these elements are called intronic splice silencers (ISS) and enhancers (ISE); exonic splice silencers (ESS) and enhancers (ESE). b A depiction of the enrichment of consensus cis-elements bound by various trans-acting factors acting in a coordinated manner to regulate alternative splicing of multiple transcripts during myogenesis. The upstream or downstream binding of the trans-acting factors relative to the alternative exon dictates its inclusion or exclusion. Protein mentioned in the box are some of the trans-acting factors that regulate muscle-specific alternative splicing and are differentially expressed during the course of myogenesis

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  Fig. 3. Tissue-specific regulation of pre-mRNA splicing. During myogenesis, induced expression of RBFOX1 and RBFOX2, which binds to the consensus downstream intronic element, promotes the production of the Mef2Dα2 alternative spliced variant. MEF2Dα2 facilitates the expression of late differentiation genes to support the formation of myotubes

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  Fig. 4. Alternative splicing of contractile protein gene tropomyosin. Tropomyosin undergoes cell type-specific alternative splicing and regulates muscle contraction. Exons 2 and 3 are mutually exclusive, and transcript with exon 3 is skeletal muscle specific. Also, the inclusion of SM exon is skeletal muscle specific, while NM exon is included in non-muscle cells. The inclusion of exons 9a and 9b of tropomyosin transcript is unique for isoforms of the skeletal muscle. Cell type-specific inclusion of exons alters the affinity with and polymerization of actin filaments, contributing to altered muscle contraction

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  Fig. 5. Alternative splicing of genes involved in excitation-contraction coupling. Acetylcholine secreted from the synaptic nerve ends binds to acetylcholine receptors and generates an action potential that transmits through T-tubule, activating ryanodine receptors to efflux Ca2+ from sarcoplasmic reticulum and SERCA channels facilitate influx of Ca2+. Ryanodine receptor and SERCA channel transcripts undergo “fetal-to-adult” temporal shift in alternative splicing at exons 29 and 33 and exon 22, respectively. Fetal splice variants of RyR1 and SERCA (also observed in DM pathogenesis) are less efficient in ATPase and Ca2+ handling

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  Fig. 6. Alternative splicing in Duchenne muscular dystrophy. a Genomic organization of dystrophin gene locus. b Aberrant alternative splicing results in the formation of “out-of-frame” transcripts that cannot encode for functional dystrophin, causing Duchenne muscular dystrophy (DMD). c However, some of the splicing events also yield “in-frame” transcripts that can encode for partially functional dystrophin, the phenotype of which is called Beckers’ syndrome or Becker muscular dystrophy (BMD)