Evolutionary divergence of basal and activity-dependent exon splicing in cortical neurons

Dando, O.; Qiu, J.; Chandran, S.; Hardingham, G. E.

doi:10.1101/2022.12.29.522197

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bioRxiv · 10.1101/2022.12.29.522197

Evolutionary divergence of basal and activity-dependent exon splicing in cortical neurons

Dando, O.·Qiu, J.·Chandran, S.·Hardingham, G. E.

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Abstract

Alternative splicing of mRNA exons in mammalian neurons increases diversity of the proteome and is regulatable by signaling pathways. However, the degree of conservation of basal and signal-dependent exon usage between human neurons and those from experimental models such as mice is incompletely understood. We previously showed that cortical neuronal activity-dependent gene transcription exhibits human/mouse differences, driven by evolutionary divergence of cis-acting promoter elements (Qiu et al. 2016). Since alternative exon usage influences brain development and cognition, is controlled by neuronal activity, and is disturbed in brain disorders, we investigated human/mouse differences in exon usage in cortical neurons. Comparing orthologous exons, basal exon inclusion levels showed human-mouse conservation, but also significant differences determined by cis-acting sequences: human-mouse conservation and divergence in exon usage was recapitulated in neurons from Tc1 mice carrying human chromosome-21 (hCh21). Activity-dependent changes in exon usage also exhibited significant conservation: gene structure was more likely to be conserved in activity-regulated exons, and exons regulated in both human and mouse neurons were enriched in RBFOX and SAM68 targets, and genes were centred on cytoskeletal organisation, mRNA transcription/processing, and synaptic signaling. However, divergence was also evident, and human-specific activity-dependent exon usage was dominated by genes involved in lipid biosynthesis, signaling and trafficking. Notably, the pattern of activity-dependent usage of hCh21 exons in human neurons was not recapitulated in mouse Tc1 neurons. Thus, unlike species-specific differences in activity-dependent gene transcription, cis-acting DNA sequence divergence is insufficient to explain inter-species differences in activity-regulated exon usage. Trans-acting factors involved in activity-responsive splicing have likely also diverged.

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Dando, O., Qiu, J., Chandran, S., Hardingham, G. E.. 2022-12-29. Evolutionary divergence of basal and activity-dependent exon splicing in cortical neurons. https://doi.org/10.1101/2022.12.29.522197

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