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Modular Organization of Cis-regulatory Control Information of Neurotransmitter Pathway Genes in Caenorhabditis elegans

Here, Serrano-Saiz et al. describe the cis-regulatory logic of how neurotransmitter identity is imposed onto individual, distinct neuron types... We explore here the cis-regulatory logic that dictates gene expression in specific cell types in the nervous system. We focus on a set of eight genes involved in the synthesis, transport, and breakdown of three neurotransmitter systems: acetylcholine (unc-17/VAChT, cha-1/ChAT, cho-1/ChT, and ace-2/AChE), glutamate (eat-4/VGluT), and γ-aminobutyric acid (unc-25/GAD, unc-46/LAMP, and unc-47/VGAT). These genes are specifically expressed in defined subsets of cells in the nervous system. Through transgenic reporter gene assays, we find that the cellular specificity of expression of all of these genes is controlled in a modular manner through distinct cis-regulatory elements, corroborating the previously inferred piecemeal nature of specification of neurotransmitter identity. This modularity provides the mechanistic basis for the phenomenon of “phenotypic convergence,” in which distinct regulatory pathways can generate similar phenotypic outcomes (i.e., the acquisition of a specific neurotransmitter identity) in different neuron classes. We also identify cases of enhancer pleiotropy, in which the same cis-regulatory element is utilized to control gene expression in distinct neuron types. We engineered a cis-regulatory allele of the vesicular acetylcholine transporter, unc-17/VAChT, to assess the functional contribution of a “shadowed” enhancer. We observed a selective loss of unc-17/VAChT expression in one cholinergic pharyngeal pacemaker motor neuron class and a behavioral phenotype that matches microsurgical removal of this neuron. Our analysis illustrates the value of understanding cis-regulatory information to manipulate gene expression and control animal behavior.