RT Journal Article SR Electronic T1 Modular Splicing Is Linked to Evolution in the Synapse-Specificity Molecule Kirrel3 JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0253-23.2023 DO 10.1523/ENEURO.0253-23.2023 VO 10 IS 12 A1 Traenkner, Dimitri A1 Shennib, Omar A1 Johnson, Alyssa A1 Weinbrom, Adam A1 Taylor, Matthew R. A1 Williams, Megan E. YR 2023 UL http://www.eneuro.org/content/10/12/ENEURO.0253-23.2023.abstract AB Kirrel3 is a cell-adhesion molecule that instructs the formation of specific synapses during brain development in mouse and Kirrel3 variants may be risk factors for autism and intellectual disabilities in humans. Kirrel3 is predicted to undergo alternative splicing but brain isoforms have not been studied. Here, we present the first in-depth characterization of Kirrel3 isoform diversity in brain using targeted, long-read mRNA sequencing of mouse hippocampus. We identified 19 isoforms with predicted transmembrane and secreted forms and show that even rare isoforms generate detectable protein in the brain. We also analyzed publicly-available long-read mRNA databases from human brain tissue and found 11 Kirrel3 isoforms that, similar to mouse, encode transmembrane and secreted forms. In mice and humans, Kirrel3 diversity arises from alternative, independent use of protein-domain coding exons and alternative early translation-stop signals. Intriguingly, the alternatively spliced exons appear at branch points in the chordate phylogenetic tree, including one exon only found in humans and their closest living relatives, the great apes. Together, these results validate a simple pipeline for analyzing isoform diversity in genes with low expression and suggest that Kirrel3 function is fine-tuned by alternative splicing and may play a role in brain evolution.