The kpc-1 (furin) 3’UTR promotes dendritic transport and local translation of mRNAs to regulate dendrite branching and self-avoidance of a nociceptive neuron

Summary Mechanical stimuli on the skin of C. elegans are detected by the dendritic arbors of PVD nociceptive neurons, which provide uniform sensory coverage outside the head region across the entire animal. Through genetic screens, we isolate three mutants that display profound dendrite self-avoidance defects in PVD neurons. Studying dendrite self-avoidance in C. elegans is likely to provide new mechanistic insight into the process as the well-known self-avoidance molecule Dscam is absent from the C. elegans genome. Through whole genome sequencing, we identify the responsible mutations in the kpc-1 gene. Compared to wild-type animals, a strong kpc-1 mutant allele exhibits secondary dendrite branching defects whereas a weak kpc-1 mutant allele displays tertiary dendrite self-avoidance defects. Here, we show that the kpc-1 3’UTR is required for kpc-1 ’s functions in both dendrite branching and dendrite self-avoidance. The kpc-1 3’UTR facilitates kpc-1 RNA localization to branching points and contact points between sibling dendrites. Using fluorescence recovery after photoconversion, we show that the kpc-1 3’UTR promotes local protein synthesis in the distal segment of PVD dendrites. We identify an important secondary structural motif in the kpc-1 3’UTR required for tertiary dendrite self-avoidance. We demonstrate that over-expression of kpc-1 leads to greater self-avoidance without limiting initial dendrite outgrowth, supporting a direct role of kpc-1 in self-avoidance. Animals with dma-1 receptor over-expression display similar secondary dendrite branching and tertiary dendrite self-avoidance defects that are suppressed with kpc-1 over-expression, which suggests that DMA-1 is a potential KPC-1 target that is down-regulated by KPC-1. Our results support a model where KPC-1 proteins are synthesized at branching points and contact points between neighboring dendrites to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance. A recently reported Schizophrenia-associated genetic variant in the 3’UTR of the human furin gene, a homolog of kpc-1 , highlights the important role of the kpc-1 (furin) 3’UTR in neuronal development, which is further demonstrated by this mechanistic study.