Li, L., Ding, Z., Pang, T.L., Zhang, B., Li, C.H., Liang, A.M., Wang, Y.R., Zhou, Y., Fan, Y.J., Xu, Y.Z. (2020). Defective minor spliceosomes induce SMA-associated phenotypes through sensitive intron-containing neural genes in Drosophila.  Nat. Commun. 11(1): 5608.

FBrf0247174

Research paper

The minor spliceosome is evolutionarily conserved in higher eukaryotes, but its biological significance remains poorly understood. Here, by precise CRISPR/Cas9-mediated disruption of the U12 and U6atac snRNAs, we report that a defective minor spliceosome is responsible for spinal muscular atrophy (SMA) associated phenotypes in Drosophila. Using a newly developed bioinformatic approach, we identified a large set of minor spliceosome-sensitive splicing events and demonstrate that three sensitive intron-containing neural genes, Pcyt2, Zmynd10, and Fas3, directly contribute to disease development as evidenced by the ability of their cDNAs to rescue the SMA-associated phenotypes in muscle development, neuromuscular junctions, and locomotion. Interestingly, many splice sites in sensitive introns are recognizable by both minor and major spliceosomes, suggesting a new mechanism of splicing regulation through competition between minor and major spliceosomes. These findings reveal a vital contribution of the minor spliceosome to SMA and to regulated splicing in animals.

PMC7644725 (PMC) (EuropePMC)