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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.

Dopamine-dependent, swimming-induced paralysis arises as a consequence of loss of function mutations in the RUNX transcription factor RNT-1