Like hundreds of Drosophila genes, Dscam1 generates alternative length 3´ UTR isoforms via alternative polyadenylation, with the longer isoform more abundant in neural tissues.
We used shRNA and CRISPR approaches to eliminate this long 3′ UTR isoform in Drosophila. These flies have compromised axon outgrowth.
We found that Dscam1 long 3′ UTR isoforms harbor distinct upstream protein coding exons using Nanopore MinION sequencing.
The RNA binding protein Elav regulates both the skipping of exon 19 and biogenesis of the long 3′ UTR. It turns out that the long 3′ UTR is required for proper alternative splicing of exon 19. So, in a way, the end determines the middle. Pre-mRNA looping perhaps? Excited to figure out that next.
Why does this matter?
There are hundreds of alternative, neural-expressed long 3´ UTR isoforms in flies, and thousands in humans. Their functions are largely unknown. Here, we showed that the long 3´ UTR version of Dscam1 is essential for nervous system function.
Lots of genes undergo alternative splicing and alternative polyadenylation. But for Dscam1, these events are very precisely linked via Elav regulation.
Identifying how upstream exons are connected to alternative 3´ UTRs is now possible with long read sequencing technology. It is likely that other genes are regulated in this fashion with specific protein coding exons matching with specific 3´ UTRs.
Read the paper in Cell Reports: