Conserved role of unc-79 in ethanol responses in lightweight mutant mice.
The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt), disrupts the homolog of the Caenorhabditis elegans (C. elegans) unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants suggests a novel conserved pathway that might influence alcohol-related behaviors in humans.
Speca
David J
DJ
Department of Neurology and the Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, United States of America. dave.speca@gmail.com
Chihara
Daisuke
D
Ashique
Amir M
AM
Bowers
M Scott
MS
Pierce-Shimomura
Jonathan T
JT
Lee
Jungsoo
J
Rabbee
Nusrat
N
Speed
Terence P
TP
Gularte
Rodrigo J
RJ
Chitwood
James
J
Medrano
Juan F
JF
Liao
Mark
M
Sonner
James M
JM
Eger
Edmond I
EI
Peterson
Andrew S
AS
McIntire
Steven L
SL
D000818:Animals; D001835:Body Weight; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D007473:Ion Channels; D008565:Membrane Proteins; C519922:NALCN protein, mouse; D009419:Nerve Tissue Proteins; C553878:UNC-79 protein, mouse; C520111:Unc-79 protein, C elegans; D000431:Ethanol