Degenerin/epithelial sodium channels (DEG/ENaC) represent a large family of animal-specific membrane proteins. Although the physiological functions of most family members are not known, some have been shown to act as nonvoltage gated, amiloride-sensitive sodium channels. The DEG/ENaC family is exceptionally large in genomes of Drosophila species relative to vertebrates and other insects. To elucidate the evolutionary history of the DEG/ENaC family in Drosophila, we took advantage of the genomic and genetic information available for 12 Drosophila species that represent all the major species groups in the Drosophila clade. We have identified 31 family members (termed pickpocket genes) in Drosophila melanogaster, which can be divided into six subfamilies, which are represented in all 12 species. Structure prediction analyses suggested that some subunits evolved unique structural features in the large extracellular domain, possibly supporting mechanosensory functions. This finding is further supported by experimental data that show that both ppk1 and ppk26 are expressed in multidendritic neurons, which can sense mechanical nociceptive stimuli in larvae. We also identified representative genes from five of the six DEG/ENaC subfamilies in a mosquito genome, suggesting that the core DEG/ENaC subfamilies were already present early in the dipteran radiation. Spatial and temporal analyses of expression patterns of the various pickpocket genes indicated that paralogous genes often show very different expression patterns, possibly indicating that gene duplication events have led to new physiological or cellular functions rather than redundancy. In summary, our analyses support a rapid early diversification of the DEG/ENaC family in Diptera followed by physiological and/or cellular specialization. Some members of the family may have diversified to support the physiological functions of a yet unknown class of ligands.

This article is available online at http://www.jlr.org Cardiovascular disease (CVD) has a complex etiology and is the leading cause of death in the United States ( 1 ). Risk factors for CVD include dyslipidemia (e.g., high plasma cholesterol and triglycerides), elevated blood pressure (e.g., hypertension), and obesity [e.g., body mass index (BMI) > 30.0 kg/m 2 ]. These factors have strong environmental contributions, including whether an individual smokes, activity level, and percentage of dietary saturated fat ( 2 ). Heritability estimates for the risk factors of CVD indicate there is a strong genetic contribution as well, and heritabilities vary between the sexes as well as within and across ethnic populations ( 3 ). Many candidate genes for CVD risk factors have been identifi ed in human linkage and in genome-wide association studies (GWAS) ( 4 ). However, these genes account for a very small proportion of the overall heritable variation of risk, approximately 5-10% cumulatively ( 5 ). This is due partly to the confounding factors of genetic and environmental heterogeneity in human populations and partly to the lack of statistical power to detect genes with small phenotypic effects, those genes that underlie much of the variation in complex traits, such as circulating lipid levels, blood pressure, and obesity.Despite not developing CVD per se, mice have nevertheless made major contributions to our knowledge of disease etiology, particularly in our understanding of disease physiology and in our identifi cation of genetic risk factors. This is because phenotypes are ascertained in controlled environments and large numbers of offspring are generated

SummaryThe response of individual animals to mating signals depends on the sexual identity of the individual and the genetics of the mating targets, which represent the mating social context (social environment). However, how social signals are sensed and integrated during mating decisions remains a mystery. One of the models for understanding mating behaviors in molecular and cellular terms is the male courtship ritual in the fruit fly (Drosophila melanogaster). We have recently shown that a subset of gustatory receptor neurons (GRNs) that are enriched in the male appendages and express the ion channel ppk23 play a major role in the initiation and maintenance of male courtship via the perception of cuticular contact pheromones, and are likely to represent the main chemosensory pathway that influences mating decisions by males. Here we show that genetic feminization of ppk23-expressing GRNs in male flies resulted in a significant increase in male–male sexual attraction without an apparent impact on sexual attraction to females. Furthermore, we show that this increase in male–male sexual attraction is sensory specific, which can be modulated by variable social contexts. Finally, we show that feminization of ppk23-expressing sensory neurons lead to major transcriptional shifts, which may explain the altered interpretation of the social environment by feminized males. Together, these data indicate that the sexual cellular identity of pheromone sensing GRNs plays a major role in how individual flies interpret their social environment in the context of mating decisions.

Optimal mating decisions depend on stable signaling systems because any independent changes in either the signal or its perception could carry a fitness cost. However, since the perception and production of specific mating signals are often mediated by different tissues and cell types, the genetic and cellular mechanisms that drive and maintain their coupling on the evolutionary and physiological timescales remain unknown for most animal species. Here, we show that in Drosophila melanogaster, sensory perception and synthesis of an inhibitory mating pheromone is regulated by the action of Gr8a, a member of the Gustatory receptor gene family. Particularly, Gr8a acts as a pheromone chemoreceptor in the sensory system of males and females, and, independently regulates pheromone synthesis in the male fat body and oenocytes. These data provide a relatively simple molecular explanation for how genetic coupling allows for the robust and stable flow of social information at the population level.

Optimal mating decisions depend on the robust coupling of signal production and perception because independent changes in either could carry a fitness cost. However, since the perception and production of mating signals are often mediated by different tissues and cell types, the mechanisms that drive and maintain their coupling remain unknown for most animal species. Here, we show that in Drosophila, sensory perception and production of an inhibitory mating pheromone are co-regulated by Gr8a, a member of the Gustatory receptor gene family. Specifically, we found that the pleiotropic action of Gr8a independently regulates the perception of pheromones by the chemosensory systems of males and females, as well as their production in the fat body and oenocytes of males. These findings provide a relatively simple molecular explanation for how pleiotropic receptors maintain robust mating signaling systems at the population and species levels.