Defective minor spliceosomes induce SMA-associated phenotypes through sensitive intron-containing neural genes in Drosophila

Liang Li, Zhan Ding, Ting-Lin Pang, Bei Zhang, Chen-Hui Li, An-Min Liang, Yu-Ru Wang, Yu Zhou, Yu-Jie Fan () and Yong-Zhen Xu ()
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Liang Li: Chinese Academy of Sciences
Zhan Ding: Chinese Academy of Sciences
Ting-Lin Pang: Chinese Academy of Sciences
Bei Zhang: Chinese Academy of Sciences
Chen-Hui Li: Wuhan University
An-Min Liang: Wuhan University
Yu-Ru Wang: Chinese Academy of Sciences
Yu Zhou: Wuhan University
Yu-Jie Fan: Wuhan University
Yong-Zhen Xu: Wuhan University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19451-z

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