Dong, H., Xu, B., Wu, L., Wang, Z., Li, Z., Xie, J., Lv, J., Yang, W., Bao, N., Qu, H., Fu, J., Yan, R., Wang, Y., Li, L., Shi, F., Huang, J., Yang, X., Jin, Y. (2026). Regulatory paradigm of Dscam1 stochastic alternative splicing through conserved long-range RNA structures.  Nucleic Acids Res. 54(5): gkag157.

FBrf0264824

Research paper

Pancrustacean Dscam1 genes encode 2 000-120 000 distinct isoforms via mutually exclusive splicing; however, the underlying regulatory mechanisms are not fully understood. Here, we revealed a regulatory paradigm of stochastic Dscam1 alternative splicing mediated by conserved long-range RNA structures over 450 million years of evolution. By integrating comparative genomic analysis with mutational evidence, we defined two distinct, evolutionarily conserved RNA structures-the balancer RNA structure and a multi-subunit RNA architecture-that drive the stochastic selection of variable exon 6. The former balances stochastic selection of variable exon 6 isoforms via RNA structural spatial compensation, while the latter acts as a temporal splicing rheostat to counteract the ''window of opportunity'' for the splicing of 5'-proximal exon 6 variants. Genetic analyses further indicate that these RNA structural elements are essential for proper development and neural wiring. Thus, we proposed a regulatory model in which multiplexed RNA secondary structures coordinate temporally and spatially to orchestrate the stochastic selection of variable exon 6 isoforms. Our findings reveal a new regulatory paradigm of alternative splicing through RNA structural dynamics in cellular processes.

PMC12962786 (PMC) (EuropePMC)