Elav-mediated exon skipping and alternative polyadenylation of the Dscam1 gene is required for axon outgrowth

Many metazoan genes express alternative long 3' UTR isoforms in the nervous system, but their functions remain largely unclear. In Drosophila melanogaster, the Dscam1 gene generates short and long (Dscam1-L) 3' UTR isoforms due to alternative polyadenylation (APA). Here, we found that the RNA-binding protein Embryonic Lethal Abnormal Visual System (Elav) impacts Dscam1 biogenesis at two levels, including regulation of long 3' UTR biogenesis and skipping of an upstream exon (exon 19). MinION long-read sequencing confirmed the connectivity of this alternative splicing event to the long 3' UTR. Knockdown or CRISPR deletion of Dscam1-L impaired axon growth in Drosophila. The Dscam1 long 3' UTR was found to be required for correct Elav-mediated skipping of exon 19. Elav thus co-regulates APA and alternative splicing to generate specific Dscam1 transcripts that are essential for neural development. This coupling of APA to alternative splicing might represent a new class of regulated RNA processing.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC=\"FIGDIR/small/613059_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (45K):\norg.highwire.dtl.DTLVardef@1a23558org.highwire.dtl.DTLVardef@5c3dddorg.highwire.dtl.DTLVardef@1e1808forg.highwire.dtl.DTLVardef@1bf3888_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIElav regulates Dscam1 long 3' UTR (Dscam1-L) biogenesis\nC_LIO_LILong-read sequencing reveals connectivity of long 3' UTR to skipping of upstream exon 19\nC_LIO_LILoss of Dscam1-L impairs axon outgrowth\nC_LIO_LIDscam1 long 3' UTR is required for correct splicing of exon 19\nC_LI