Developmentally-regulated splice remodeling shapes functional CACNA1C channel diversity during human neurodevelopment

Long-read RNA sequencing during differentiation of human induced pluripotent stem cells into cortical glutamatergic neurons identifies 60 CACNA1C isoforms, with developmentally regulated exon-switching between exon pairs 8/8a, 21/22, and 31/32.

• Why it matters: How CACNA1C splicing is controlled in early human neurodevelopment is unclear, despite CACNA1C being a major regulator of neuronal calcium signaling and a strong psychiatric risk locus.
• What they did: The study profiled full-length CACNA1C transcripts across differentiation from healthy controls and bipolar disorder patients homozygous for A or G at rs1006737 using long-read RNA sequencing, then validated splice trajectories in dorsal forebrain organoids.
• The result: Exon 31/32 switching is linked to altered CaV1.2 channel inactivation properties in electrophysiological tests of the two most abundant neuronal isoforms, while rs1006737 genotype, diagnosis, sex, and age did not significantly change splicing profiles.

AI summary of the abstract · may contain errors · not medical advice · read the paper.