The Alternative Splicing Regulator Tra2b Is Required for Somitogenesis and Regulates Splicing of an Inhibitory Wnt11b Isoform

• Published in: Cell reports (Cambridge) Vol. 10; no. 4; pp. 527 - 536
• Main Authors: Dichmann, Darwin S., Walentek, Peter, Harland, Richard M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-02-2015; Elsevier
• Subjects: Alternative Splicing - genetics; Alternative Splicing - physiology; Animals; Animals, Genetically Modified; Protein Isoforms - genetics; Protein Isoforms - metabolism; RNA Splicing - genetics; RNA Splicing - physiology; Somites - cytology; Somites - metabolism; Wnt Proteins - genetics; Wnt Proteins - metabolism; Xenopus; Xenopus laevis; Xenopus Proteins - genetics; Xenopus Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.12.046

Alternative splicing is pervasive in vertebrates, yet little is known about most isoforms or their regulation. transformer-2b (tra2b) encodes a splicing regulator whose endogenous function is poorly understood. Tra2b knockdown in Xenopus results in embryos with multiple defects, including defective somitogenesis. Using RNA sequencing, we identify 142 splice changes (mostly intron retention and exon skipping), 89% of which are not in current annotations. A previously undescribed isoform of wnt11b retains the last intron, resulting in a truncated ligand (Wnt11b-short). We show that this isoform acts as a dominant-negative ligand in cardiac gene induction and pronephric tubule formation. To determine the contribution of Wnt11b-short to the tra2b phenotype, we induce retention of intron 4 in wnt11b, which recapitulates the failure to form somites but not other tra2b morphant defects. This alternative splicing of a Wnt ligand adds intricacy to a complex signaling pathway and highlights intron retention as a regulatory mechanism.
[Display omitted]
•Tra2b knockdown causes multiple developmental defects, including in somitogenesis•Tra2b knockdown results in intron retention and exon skipping•Intron retention in wnt11b produces a truncated inhibitory ligand•The inhibitory Wnt11b ligand inhibits somitogenesis
Alternative splicing is pervasive in vertebrates, but the function and regulation of most isoforms are unknown. Here, Dichmann et al. show that the splicing regulator Tra2b is critical for embryogenesis and somite formation. Tra2b regulates an intron retention event in wnt11b, which produces a truncated ligand that inhibits somitogenesis.