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Title: Conserved Role of unc-79 in Ethanol Responses in Lightweight Mutant Mice}
Article:
Abstract:
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.
Introduction:
Alcohol is enjoyed by many, but its abuse can lead to enormous adverse individual and societal consequences. According to the World Health Organization, alcohol abuse accounts for 4% of the global health burden[1]. While twin, adoption, and family studies suggest that there is a strong genetic component to alcoholism[2],[3], identifying susceptibility factors in human populations is difficult because of the heterogeneity of the disorder and the likelihood that there are multiple genes of small effect that contribute to the disease. Invertebrate genetic screens have identified several genes with clear effects on response to ethanol and inhaled anesthetics. In Caenorhabditis elegans( C. elegans), for example, unc-79( and unc-80) mutants are hypersensitive to the immobilizing effects of halothane and other anesthetic agents[4],[5]. In addition, unc-79 mutants are also reported to have altered responses to the immobilizing effects of ethanol[6]. In Drosophila melanogaster( Drosophila), Krishnan and Nash identified an allele of the narrow abdomen( na) gene in a forward mutagenesis screen for halothane sensitivity[7]. The na gene product has the predicted topology of a voltage-gated cationic channel[8] but efforts to characterize it electrophysiologically were unsuccessful until recently when Ren and colleagues proposed that the mouse homolog of this channel, which they named NALCN, was a tetrodotoxin-insensitive, voltage-independent cationic( leak) channel that may be critical for altering the resting membrane potential of neurons[9]. A mouse homozygous knockout allele of the NALCN gene was perinatal lethal, perhaps due to a respiratory defect[9]. Numerous studies suggest that unc-79, unc-80, and NALCN, function in the same biochemical pathway. In both C. elegans and Drosophila, for instance, mutants exhibit altered locomotor behavior( “fainting” in worms and hesitant walking in flies) and have altered responses to anesthetics[10]. In addition, the protein expression of these gene products is interdependent, i. e. disruption of unc-79 or unc-80 also yields lower or absent expression of NALCN orthologs and vice versa, leading to the hypothesis that they function as a complex[10]–[14]. Most compelling is recent data demonstrating that the function of the NALCN protein can be modulated by the peptide neurotransmitters substance P and neurotensin and that the unc-80 gene product is required to mediate this signal transduction pathway[13],[14]. Others have demonstrated in vitro that the M3 muscarinic receptor can activate the NALCN channel[15]. Together, these data indicate that the NALCN channel and associated proteins may be responsible for a ‘slow’ excitation that can be evoked by substance P, neurotensin, acetylcholine or norepinehprine[16]–[18]. Not only has forward mutagenesis been an invaluable approach in C. elegans and Drosophila for the study of the nervous system, more recent forward mutagenesis efforts in mice have isolated numerous mutants that influence a variety of behavioral phenotypes[19]–[22]. We previously performed a mouse forward mutagenesis screen using a sensitized genetic background based on a heterozygous null mutation in the dopamine transporter( DAT) to enrich for dominant mutations that enhance dopaminergic neurotransmission[23]. This screen successfully identified five loci that influence locomotor behavior in a quantitative manner, two of which were dependent on the sensitized background and three of which acted independently of the sensitized background. Here we report that the dominant behavioral phenotype of one of the independent loci, Lightweight( Lwt), results from a nonsense mutation in the mouse homolog of the C. elegans unc-79 gene. Lightweight heterozygotes are mildly hyperactive and have altered response to ethanol and inhaled anesthetics, consistent with a conserved function of the mammalian unc-79 gene product.
Discussion:
We have identified and cloned a point mutation in the mouse homolog of the unc-79 gene, to which the allele name Lightweight was assigned due to the resultant phenotypic traits. The Lightweight mutation creates a premature stop codon in the middle of the unc-79 protein. We introgressed a ∼1. 4 Mb region surrounding the Lightweight mutation fully onto the C57BL/6J genetic background. Lwt/Lwt homozogotes are born at the expected Mendelian ratios and appear normal at birth, but survive a maximum of two days, similar to what has been reported for a knockout allele of this gene[29]. Although Lightweight heterozygotes exhibit a normal birthweight, soon thereafter and as adults, body weight is significantly less than their wild-type littermates. In addition, Lightweight heterozygotes have increased lean tissue and reduced body fat in comparison to wild-type littermates. Furthermore, Lightweight heterozygotes consume more food on a B6 background and more water on a B6D2 F1 background. Together, these results suggest a higher metabolic rate, increased protein turnover, or differences in energy usage. By testing a control congenic strain in parallel, we have demonstrated that strain-specific polymorphisms from the introgressed D2 background do not produce or influence any of the phenotypes observed here. This possibility is often ignored[31] but is an important concern due to the quantitative nature of several of the phenotypes tested. Although we have ruled out strain-specific polymorphisms, we cannot formally rule out the possibility that an additional ENU-induced mutation in our congenic strain might influence some of the phenotypes we have observed. The mutation rate of ENU depends on many factors, but hovers around 1×10−6[25]–[27]; therefore, it is unlikely that more than one or two point mutations were induced within this 1. 4 Mb congenic region, and furthermore, the likelihood of mutating a coding exon is very rare[28]. We have sequenced the majority of coding exons in this congenic interval without finding any additional mutations other than Lightweight. Complete resequencing of the whole 1. 4 Mb interval would confirm the absence of other confounding mutations. The alterations that we observed in Lightweight heterozygotes in response to ethanol and anesthetics are qualitatively similar to what has been reported previously in C. elegans and Drosophila; however, important differences exist. In invertebrates, unc-79 mutants are very hypersensitive to halothane[10]; whereas, we observed no alterations in MAC for halothane in Lightweight heterozygotes. However, we did observe that Lightweight heterozgotes are resistant to isoflurane. It is unclear at this point why these species differences exist. One possibility is that most of the unc-79 alleles tested in invertebrates were true null mutations; whereas, we tested heterozygous mutant mice. Another possibility is that a truncated protein might be produced in Lightweight heterozygotes, which could interfere with the proper functioning of this pathway in unanticipated, even opposite, ways. It should be noted that the fact that Lightweight heterozygotes were resistant to isoflurane and not to all anesthetic agents tested suggests that the anesthetic phenotype does not simply reflect a non-specific alteration in neuronal function. The finding that C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants were hypersensitive to acute ethanol exposure suggests that this pathway is important for determining ethanol sensitivity. As in vertebrates, UNC-79 and UNC-80 proteins are thought to regulate the NALCN-related leak channel encoded by nca-1 and nca-2[32]. It was possible however that the ethanol phenotypes of unc-79 and unc-80 were due to additional, as yet undiscovered, roles of these genes. The fact that the nca-1;nca-2 double mutant exhibits the same ethanol hypersensitivity suggests that the normal function of this leak channel is indeed required for ethanol responses. Ethanol may directly modulate the nca-encoded leak channel or perhaps indirectly modulate the channel through an effect on unc-79 and unc-80. The ethanol hypersensitivity of Lightweight mice may also reflect defective NALCN function. Because Lightweight animals exhibited dramatically altered responses to acute ethanol injection, we assayed free choice ethanol preference and consumption using a two bottle choice test. On both a B6 and a B6D2 F1 hybrid background, Lightweight heterozygotes displayed a higher preference for and consumption of ethanol than wild-type littermates. However, on a B6D2 F1 background, in addition to having a higher preference for and consumption of ethanol( at 6% and 10%), Lightweight animals also consume more water than wild-type littermates, and when offered water or water plus a tastant( saccharin), they tend to choose the bottle containing the tastant over water alone. Given these observations, in combination with the body composition and food consumption analysis performed in B6 Lightweight animals, we favor a conservative interpretation of the two bottle choice data: Lightweight animals have a higher preference for and consumption of ethanol; however, we cannot exclude the possibility that taste preference and/or alterations in metabolism could contribute to this phenotype. Because the unc-79 protein is widely expressed throughout the central nervous system, tissue-specific deletion using conditional mutagenesis or RNA interference may yield more specific results. Nonetheless, it is clear that Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. There is a consistent correlation between rodent populations that voluntarily consume more ethanol in a two bottle choice assay and increased operant oral self administration of ethanol[33]. Because oral self administration of ethanol stimulates dopamine release[34], it is possible that the unc-79 gene product acts in the ventral tegmental area( VTA) to mediate or modulate NALCN function. In dopaminergic VTA neurons, neurotensin and other neuromodulators activate a nonselective cationic conductance with properties similar to the NALCN channel[18]. Furthermore, a neurotensin- and substance P-activated inward sodium current is absent from cultured NALCN knockout VTA neurons[13]. It is possible that ethanol acts directly upon NALCN channels in the VTA to influence firing rate. Alternatively, ethanol might alter the release of neurotensin, substance P, or other neuromodulators in the VTA to influence NALCN/unc-79 function secondarily. Testing of these hypotheses in the future may lead to insight into the mechanism of action of ethanol on the nervous system and specifically into mechanisms of reward-related behavior. In conclusion, the conservation of ethanol and anesthesia phenotypes across species suggests that unc-79 and associated unc-80 and NALCN genes are part of a novel and relatively unexplored pathway that mediates the physiological effects of these agents. It is notable that we have observed a wide variety of phenotypes in heterozygotes. If variants of unc-79 and associated genes exist in the human population, it is possible that even heterozygotes may exhibit ethanol- and weight-related phenotypes.
Alcoholism is costly to both individuals and society . Studies of twins indicate that there is a substantial genetic component to this disease; however , it has been difficult to identify underlying genetic factors in humans , in part because of the small effect of any one gene . Because of their genetic uniformity , subtle effects on behavior of single gene deletions can be detected in inbred mice and used to model human disease . Here we describe the identification of a new mouse mutant , named Lightweight , with altered response to alcohol and inhaled anesthetics . Lightweight mice are dramatically hypersensitive to a high-dose injection of alcohol . In addition , when given a choice , Lightweight mutants voluntarily consume more alcohol than non-mutant animals . Lightweight mice may provide novel insight into the mechanism of action of alcohol , and studies of this gene in humans may lead to a better understanding of alcoholism and its treatment .