Alternative splicing–triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
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Research Article Development Neuroscience

Alternative splicing–triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders

Abstract

Alternative splicing–triggered nonsense-mediated mRNA decay (AS-NMD) critically regulates gene expression, but the extent to which neuronal genes are regulated by AS-NMD remains understudied. Here, we identified over 3,000 developmentally regulated AS-NMD exons in mouse and human brains and validated them in cultured neurons. AS-NMD suppresses synaptic genes during brain development and differentially regulates more than 200 causal genes for neurodevelopmental disorders (NDDs). We detected a poison exon in GRIA2 and identified splice-switching antisense oligonucleotides that suppressed GRIA2 NMD and increased its functional isoforms. In summary, this study uncovers genes repressed by AS-NMD in the brain and nominates amenable splice-switching targets for treating dominant NDDs such as autism spectrum disorders and developmental epileptic encephalopathy.

Authors

Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang

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Figure 3

RBPs and sequence motifs associated with AS-NMD exons.

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RBPs and sequence motifs associated with AS-NMD exons. (A) Heatmap showi...
(A) Heatmap showing expression levels of 93 RBPs, binding motifs of which were significantly enriched in flanking sequences of SE-NMD events (Supplemental Figure 8). RBPs were grouped into 6 clusters based on their expression patterns during brain development. (B) PTBP binding motifs were significantly enriched within the SEs compared with the ORF_preserving Up exons. Red, test group; blue, background; dashed line, –log10 (P) from Wilcoxon’s rank-sum test. (C) Volcano plot showing differentially expressed genes upon Ptbp1/2 double KD in Neuro2a cells (n = 2 biological replicates for each condition, |log2FC| ≥ 1, adjusted P < 0.001). (D) UpSet plot illustrating the AS-NMD events that were differentially spliced in the developing mouse brain and significantly affected upon Ptbp1/2 KD. (E) The AS-NMD_in exon in Iqgap1 (chr7:80729643–80729691, mm10) showed higher inclusion in E18.5 and in shPtbp1/2 cells. (F) The AS-NMD_ex Rock1 exon 28 (chr18:10073656–10073700) showed higher inclusion in shPtbp1/2 cells, Ptbp1/2 binding motifs, and Ptbp1/2 CLIP-seq tags.