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.
Highlights
Dopamine (DA) is a critical modulator of brain circuits that drive fundamental behaviors such as movement, habit, reward, attention, and cognition and not surprisingly, DA signaling alterations are evident in human motor disorders, such as Parkinson’s disease and dystonia, in the actions of substances of abuse [1, 2], and in disorders that feature a disruption of higher brain function, including attention-deficit/hyperactivity disorder (ADHD) [3, 4], bipolar disorder [5,6,7] and schizophrenia [8, 9]
The current report originates from our efforts to define novel, conserved determinants of DA signaling via a forward genetic approach [18, 19], whereby mutant animals are identified based on their exhibition of a readily detectible phenotype arising in the context of excess DA signaling, termed swimming-induced paralysis [20]
We have identified a novel role for the RUNX transcription factor ortholog, RNT-1, in regulating DA signaling
Summary
Dopamine (DA) is a critical modulator of brain circuits that drive fundamental behaviors such as movement, habit, reward, attention, and cognition and not surprisingly, DA signaling alterations are evident in human motor disorders, such as Parkinson’s disease and dystonia, in the actions of substances of abuse [1, 2], and in disorders that feature a disruption of higher brain function, including attention-deficit/hyperactivity disorder (ADHD) [3, 4], bipolar disorder [5,6,7] and schizophrenia [8, 9]. C. elegans DA signaling has proven suitable for both pharmacological and genetic studies of human DA modulatory genes [14,15,16] owing to the conservation of genes that encode DA synthesis, vesicular packaging, response, and inactivation [17]. The current report originates from our efforts to define novel, conserved determinants of DA signaling via a forward genetic approach [18, 19], whereby mutant animals are identified based on their exhibition of a readily detectible phenotype arising in the context of excess DA signaling, termed swimming-induced paralysis [20]. An inability to clear synaptic DA, in the context of significant DA release triggered by immersion of worms in water, leads to extrasynaptic actions of DA on the D2-type DA receptor DOP-3 that inhibit the activity of motorneurons, leading to paralysis
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