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 2

Dynamic AS-NMD in the developing mouse brain.

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Dynamic AS-NMD in the developing mouse brain. (A) PCA of PSI values from...
(A) PCA of PSI values from dynamic SE events (0.03 < minimum PSI of all samples < 0.95, n = 22,464) across the developing and adult mouse brains and other adult tissues (2 biological replicates for each group). (B) Predicted AS-NMD events that were differentially spliced across different embryonic stages or between the adult mouse brain and other adult tissues. (C) UpSet plot summarizing SE-NMD events in developing and adult mouse brains, as well as long read–supported SE-NMD events (E14.5/E18.5), GENCODE M25, and UCSC cassette exons. (D) Heatmap of the top 15 developmentally upregulated (from E11.5 to E18.5 brains) and top 15 downregulated NMD_in SE exons showing their PSI (splicing, left) and TPM (gene expression, right) changes during mouse brain development. CTX, cortex; CB, cerebellum. (E) Gene Ontology and biological process (BP) term enrichment of genes carrying NMD_in exons. (F) RT-PCR validation and quantification of NMD_in events in mouse E11.5 and E18.5 dorsal forebrains. Numbers indicate PSI values. For all shown events, 2-tailed t test P < 0.05, n = 3 biological replicates per group. (G) RT-PCR validation and quantification of NMD_in events in mouse primary neurons treated with CHX. Numbers indicate PSI values. For events, 2-tailed t test P < 0.05, n = 3 biological replicates per group.