Sci Adv.: co-auth.: group Roignant

Sci Adv. 2022 Jan 28;8(4):eabk0445. doi: 10.1126/sciadv.abk0445. Epub 2022 Jan 28.

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Antonio Torres-Méndez 1 2Sinziana Pop 2Sophie Bonnal 1Isabel Almudi 3 4Alida Avola 2Ruairí J V Roberts 2Chiara Paolantoni 5Ana Alcaina-Caro 3Ane Martín-Anduaga 6Irmgard U Haussmann 7Violeta Morin 8Fernando Casares 3Matthias Soller 9 10Sebastian Kadener 6Jean-Yves Roignant 5 11Lucia Prieto-Godino 2Manuel Irimia 1 12 13


Alternative splicing increases neuronal transcriptomic complexity throughout animal phylogeny. To delve into the mechanisms controlling the assembly and evolution of this regulatory layer, we characterized the neuronal microexon program in Drosophila and compared it with that of mammals. In nonvertebrate bilaterians, this splicing program is restricted to neurons by the posttranscriptional processing of the enhancer of microexons (eMIC) domain in Srrm234. In Drosophila, this processing is dependent on regulation by Elav/Fne. eMIC deficiency or misexpression leads to widespread neurological alterations largely emerging from impaired neuronal activity, as revealed by a combination of neuronal imaging experiments and cell type-specific rescues. These defects are associated with the genome-wide skipping of short neural exons, which are strongly enriched in ion channels. We found no overlap of eMIC-regulated exons between flies and mice, illustrating how ancient posttranscriptional programs can evolve independently in different phyla to affect distinct cellular modules while maintaining cell-type specificity.