Identifying sexual differentiation genes that affect Drosophila life span

BACKGROUND Sexual differentiation often has significant effects on life span and aging phenotypes. For example, males and females of several species have different life spans, and genetic and environmental manipulations that affect life span often have different magnitude of effect in males versus females. Moreover, the presence of a differentiated germ-line has been shown to affect life span in several species, including Drosophila and C. elegans. METHODS Experiments were conducted to determine how alterations in sexual differentiation gene activity might affect the life span of Drosophila melanogaster. Drosophila females heterozygous for the tudor[1] mutation produce normal offspring, while their homozygous sisters produce offspring that lack a germ line. To identify additional sexual differentiation genes that might affect life span, the conditional transgenic system Geneswitch was employed, whereby feeding adult flies or developing larvae the drug RU486 causes the over-expression of selected UAS-transgenes. RESULTS In this study germ-line ablation caused by the maternal tudor[1] mutation was examined in a long-lived genetic background, and was found to increase life span in males but not in females, consistent with previous reports. Fitting the data to a Gompertz-Makeham model indicated that the maternal tudor[1] mutation increases the life span of male progeny by decreasing age-independent mortality. The Geneswitch system was used to screen through several UAS-type and EP-type P element mutations in genes that regulate sexual differentiation, to determine if additional sex-specific effects on life span would be obtained. Conditional over-expression of transformer female isoform (traF) during development produced male adults with inhibited sexual differentiation, however this caused no significant change in life span. Over-expression of doublesex female isoform (dsxF) during development was lethal to males, and produced a limited number of female escapers, whereas over-expression of dsxF specifically in adults greatly reduced both male and female life span. Similarly, over-expression of fruitless male isoform A (fru-MA) during development was lethal to both males and females, whereas over-expression of fru-MA in adults greatly reduced both male and female life span. CONCLUSION Manipulation of sexual differentiation gene expression specifically in the adult, after morphological sexual differentiation is complete, was still able to affect life span. In addition, by manipulating gene expression during development, it was possible to significantly alter morphological sexual differentiation without a significant effect on adult life span. The data demonstrate that manipulation of sexual differentiation pathway genes either during development or in adults can affect adult life span.