RRC ID 59581
著者 Robinson SB, Refai O, Hardaway JA, Sturgeon S, Popay T, Bermingham DP, Freeman P, Wright J, Blakely RD.
タイトル Dopamine-dependent, swimming-induced paralysis arises as a consequence of loss of function mutations in the RUNX transcription factor RNT-1.
ジャーナル PLoS One
Abstract Dopamine (DA) is a neurotransmitter with actions across phylogeny that modulate core behaviors such as motor activity, reward, attention, and cognition. Perturbed DA signaling in humans is associated with multiple disorders, including addiction, ADHD, schizophrenia, and Parkinson's disease. The presynaptic DA transporter exerts powerful control on DA signaling by efficient clearance of the neurotransmitter following release. As in vertebrates, Caenorhabditis elegans DAT (DAT-1) constrains DA signaling and loss of function mutations in the dat-1 gene result in slowed crawling on solid media and swimming-induced paralysis (Swip) in water. Previously, we identified a mutant line, vt34, that exhibits robust DA-dependent Swip. vt34 exhibits biochemical and behavioral phenotypes consistent with reduced DAT-1 function though vt34; dat-1 double mutants exhibit an enhanced Swip phenotype, suggesting contributions of the vt34-associated mutation to additional mechanisms that lead to excess DA signaling. SNP mapping and whole genome sequencing of vt34 identified the site of the molecular lesion in the gene B0412.2 that encodes the Runx transcription factor ortholog RNT-1. Unlike dat-1 animals, but similar to other loss of function rnt-1 mutants, vt34 exhibits altered male tail morphology and reduced body size. Deletion mutations in both rnt-1 and the bro-1 gene, which encodes a RNT-1 binding partner also exhibit Swip. Both vt34 and rnt-1 mutations exhibit reduced levels of dat-1 mRNA as well as the tyrosine hydroxylase ortholog cat-2. Although reporter studies indicate that rnt-1 is expressed in DA neurons, its re-expression in DA neurons of vt34 animals fails to fully rescue Swip. Moreover, as shown for vt34, rnt-1 mutation exhibits additivity with dat-1 in generating Swip, as do rnt-1 and bro-1 mutations, and vt34 exhibits altered capacity for acetylcholine signaling at the neuromuscular junction. Together, these findings identify a novel role for rnt-1 in limiting DA neurotransmission and suggest that loss of RNT-1 may disrupt function of both DA neurons and body wall muscle to drive Swip.
巻・号 14(5)
ページ e0216417
公開日 2019-1-1
DOI 10.1371/journal.pone.0216417
PII PONE-D-19-00568
PMID 31083672
PMC PMC6513266
MeSH Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / metabolism Dopamine / genetics Dopamine / metabolism* Dopaminergic Neurons / metabolism Loss of Function Mutation* Paralysis* / genetics Paralysis* / metabolism Signal Transduction / genetics Swimming* Transcription Factors* / metabolism
IF 2.776
引用数 0
リソース情報
線虫 tm2661 tm388 tm1183