Language
English
Publication Date
12-1-2025
Journal
RNA Biology
DOI
10.1080/15476286.2025.2491160
PMID
40207498
PMCID
PMC12064062
PubMedCentral® Posted Date
4-10-2025
PubMedCentral® Full Text Version
Post-print
Abstract
The reprogramming of alternative splicing networks during development is a hallmark of tissue maturation and identity. Alternative splicing of microexons (small, genomic regions ≤ 51 nucleotides) functionally regulate protein-protein interactions in the brain and is altered in several neuronal diseases. However, little is known about the regulation and function of alternatively spliced microexons in striated muscle. Here, we investigated alternative splicing of a microexon in the synaptosome-associated protein 23 (Snap23) encoded gene. We found that inclusion of this microexon is developmentally regulated and tissue-specific, as it occurs exclusively in adult heart and skeletal muscle. The alternative region is highly conserved in mammalian species and encodes an in-frame sequence of 11 amino acids. Furthermore, we showed that alternative splicing of this microexon is mis-regulated in mouse models of heart and skeletal muscle diseases. We identified the RNA-binding proteins (RBPs) quaking (QKI) and RNA binding fox-1 homolog 2 (RBFOX2) as the primary splicing regulators of the Snap23 microexon. We found that QKI and RBFOX2 bind downstream of the Snap23 microexon to promote its inclusion, and this regulation can be escaped when the weak splice donor is mutated to the consensus 5’ splice site. Finally, we uncovered the interplay between QKI and muscleblind-like splicing regulator (MBNL) as an additional, but minor layer of Snap23 microexon splicing control. Our results are one of the few reports detailing microexon alternative splicing regulation during mammalian striated muscle development.
Keywords
Animals, Alternative Splicing, RNA-Binding Proteins, Mice, Exons, RNA Splicing Factors, Qc-SNARE Proteins, Humans, Organ Specificity, Vesicular Transport Proteins, Muscular Diseases, Muscle, Skeletal, Muscle, Striated, Repressor Proteins, Microexon, alternative splicing, striated muscle, Snap23, RNA-binding proteins
Published Open-Access
yes
Recommended Citation
Gentile, Gabrielle M; Blue, R Eric; Goda, Grant A; et al., "Alternative Splicing of the Snap23 Microexon Is Regulated by Mbnl, Qki, and RBFOX2 in a Tissue-Specific Manner and Is Altered in Striated Muscle Diseases" (2025). Faculty and Staff Publications. 4014.
https://digitalcommons.library.tmc.edu/baylor_docs/4014
Graphical Abstract