Forward Genetic Analysis to Identify Determinants of Dopamine Signaling in Caenorhabditis elegans Using Swimming-Induced Paralysis

G3: Genes, Genomes, Genetics

Shannon L. Hardie³  Sarah M. Whitaker³  Daniel P. Bermingham³  Sarah R. Baas³  Ariana J. Lichtenstein³  Randy D. Blakely¹  J. Andrew Hardaway³  Bing Zhang² 

[1] Department of PharmacologySilvio O. Conte Center for Neuroscience ResearchDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548Department of PharmacologyDepartment of PharmacologySilvio O. Conte Center for Neuroscience ResearchDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548Silvio O. Conte Center for Neuroscience ResearchDepartment of PharmacologySilvio O. Conte Center for Neuroscience ResearchDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548Department of PharmacologySilvio O. Conte Center for Neuroscience ResearchDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548;Department of Biomedical InformaticsSilvio O. Conte Center for Neuroscience ResearchDepartment of Biomedical InformaticsDepartment of Biomedical InformaticsSilvio O. Conte Center for Neuroscience ResearchSilvio O. Conte Center for Neuroscience ResearchDepartment of Biomedical InformaticsSilvio O. Conte Center for Neuroscience Research;Department of PharmacologyDepartment of PharmacologyDepartment of Pharmacology

关键词: presynaptic;    dopamine;    transporter;    receptor;    Caenorhabditis elegans;    forward genetics;   

DOI  :  10.1534/g3.112.003533

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

Disrupted dopamine (DA) signaling is believed to contribute to the core features of multiple neuropsychiatric and neurodegenerative disorders. Essential features of DA neurotransmission are conserved in the nematode Caenorhabditis elegans, providing us with an opportunity to implement forward genetic approaches that may reveal novel, in vivo regulators of DA signaling. Previously, we identified a robust phenotype, termed Swimming-induced paralysis (Swip), that emerges in animals deficient in the plasma membrane DA transporter. Here, we report the use and quantitative analysis of Swip in the identification of mutant genes that control DA signaling. Two lines captured in our screen (vt21 and vt22) bear novel dat-1 alleles that disrupt expression and surface trafficking of transporter proteins in vitro and in vivo. Two additional lines, vt25 and vt29, lack transporter mutations but exhibit genetic, biochemical, and behavioral phenotypes consistent with distinct perturbations of DA signaling. Our studies validate the utility of the Swip screen, demonstrate the functional relevance of DA transporter structural elements, and reveal novel genomic loci that encode regulators of DA signaling.

【 授权许可】

Unknown