Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that the precisely timed lin-4-lin-14 regulatory circuit triggers an initial dendritic growth activity, whereas the precisely timed lin-28-let-7-lin-41 regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a set time frame. Loss-of-function mutations in the lin-4 microRNA gene cause limited dendritic outgrowth, whereas loss-of-function mutations in its direct target, the lin-14 transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the let-7 microRNA gene prevent a developmental decline in dendritic growth ability, whereas loss-of-function mutations in its direct target, the lin-41 tripartite motif protein gene, cause further decline. lin-4 and let-7 regulatory circuits are expressed in the right place at the right time to set start and end times for dendritic arborization. Replacing the lin-4 upstream cis-regulatory sequence at the lin-4 locus with a late-onset let-7 upstream cis-regulatory sequence delays dendrite arborization, whereas replacing the let-7 upstream cis-regulatory sequence at the let-7 locus with an early-onset lin-4 upstream cis-regulatory sequence causes a precocious decline in dendritic growth ability. Our results indicate that the lin-4-lin-14 and the lin-28-let-7-lin-41 regulatory circuits control the timing of dendrite arborization through antagonistic regulation of the DMA-1 receptor level on dendrites. The LIN-14 transcription factor likely directly represses dma-1 gene expression through a transcriptional means, whereas the LIN-41 tripartite motif protein likely indirectly promotes dma-1 gene expression through a posttranscriptional means.
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.
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