CaltechAUTHORS
  A Caltech Library Service

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

Zou, Yan and Shih, Mushaine and Chiu, Hui and Ferreira, Tarsis and Suzuki, Nobuko and Zou, Wei and Chuang, Chiou-Fen and Chang, Chieh (2021) 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. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210809-153636045

[img] PDF - Submitted Version
Creative Commons Attribution Non-commercial.

3MB
[img] PDF - Supplemental Material
Creative Commons Attribution Non-commercial.

2MB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20210809-153636045

Abstract

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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.08.03.453128DOIDiscussion Paper
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. This version posted August 5, 2021. This work was funded by grants from the March of Dimes Foundation (C.C.), the Whitehall Foundation Research Award (C.C.), the National Science Foundation (IOS-1455758 to C.C.), and the National Institute of General Medical Sciences of the National Institutes of Health (R01GM111320 to C.C.). We thank Oliver Hobert lab for Whole Genome Sequencing, Kana Hamada for confocal imaging protocols, Ryan Weihsiang Lin for imaging analysis, Seema Sheoran for unpublished observation, Evguenia Ivakhnitskaia for technical supports and critical reading the manuscript, the Caenorhabditis Genetics Center for the kpc-1(gk8) strain, and the WormBase for readily accessible information. Author Contributions: Y.Z. conceived, designed, performed, and analyzed experiments, and made constructs. M.S. conceived, designed, performed, and analyzed experiments, made constructs, and drafted the article. H.C. conceived, designed, performed, and analyzed experiments, and drafted the article. T.F. performed genetic screens, identified dendrite self-avoidance mutants, and analyzed experiments. N.Z. imaged and quantified green fluorescent MS2 capsid proteins in PVD dendrites. W.Z. made crispr line and contributed unpublished essential data and reagents. C.F.C. conceived, designed, and analyzed experiments. C.C. conceived, designed, analyzed and interpreted data, and drafted the article. The authors have declared no competing interest.
Funders:
Funding AgencyGrant Number
March of Dimes FoundationUNSPECIFIED
Whitehall FoundationUNSPECIFIED
NSFIOS-1455758
NIHR01GM111320
DOI:10.1101/2021.08.03.453128
Record Number:CaltechAUTHORS:20210809-153636045
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210809-153636045
Official Citation: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. Yan Zou, Mushaine Shih, Hui Chiu, Tarsis Ferreira, Nobuko Suzuki, Wei Zou, Chiou-Fen Chuang, Chieh Chang. bioRxiv 2021.08.03.453128; doi: https://doi.org/10.1101/2021.08.03.453128
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110164
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Aug 2021 20:25
Last Modified:16 Nov 2021 19:39

Repository Staff Only: item control page