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      The Sex Determination Gene transformer Regulates Male-Female Differences in Drosophila Body Size

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      1 , 2 , * , 2 , 1 , *
      PLoS Genetics
      Public Library of Science

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          Abstract

          Almost all animals show sex differences in body size. For example, in Drosophila, females are larger than males. Although Drosophila is widely used as a model to study growth, the mechanisms underlying this male-female difference in size remain unclear. Here, we describe a novel role for the sex determination gene transformer ( tra) in promoting female body growth. Normally, Tra is expressed only in females. We find that loss of Tra in female larvae decreases body size, while ectopic Tra expression in males increases body size. Although we find that Tra exerts autonomous effects on cell size, we also discovered that Tra expression in the fat body augments female body size in a non cell-autonomous manner. These effects of Tra do not require its only known targets doublesex and fruitless. Instead, Tra expression in the female fat body promotes growth by stimulating the secretion of insulin-like peptides from insulin producing cells in the brain. Our data suggest a model of sex-specific growth in which body size is regulated by a previously unrecognized branch of the sex determination pathway, and identify Tra as a novel link between sex and the conserved insulin signaling pathway.

          Author Summary

          Female-biased sexual size dimorphism is common in invertebrates, yet the mechanisms underlying increased female body size remain unclear. We uncovered a key role for sex determination gene transformer ( tra) in promoting increased growth in females. Interestingly, we found that sex differences in body size are regulated by Tra in a pathway that is separate of the canonical sex determination pathway, and of other aspects of sexual dimorphism. Instead, Tra function in the fat body regulates growth in a non cell-autonomous manner by regulating the secretion of insulin-like peptides from the brain. This novel Tra-insulin link we describe may have implications for other sexually dimorphic phenotypes in Drosophila ( eg. lifespan, stress resistance), many of which are also regulated by insulin.

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          Most cited references68

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          Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.

          The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030. Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations' population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries. The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people >65 years of age. These findings indicate that the "diabetes epidemic" will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.
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            Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.

            The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.
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              Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.

              The insulin/insulin-like growth factor-like signaling pathway, present in all multicellular organisms, regulates diverse functions including growth, development, fecundity, metabolic homeostasis, and lifespan. In flies, ligands of the insulin/insulin-like growth factor-like signaling pathway, the Drosophila insulin-like peptides, regulate growth and hemolymph carbohydrate homeostasis during development and are expressed in a stage- and tissue-specific manner. Here, we show that ablation of Drosophila insulin-like peptide-producing median neurosecretory cells in the brain leads to increased fasting glucose levels in the hemolymph of adults similar to that found in diabetic mammals. They also exhibit increased storage of lipid and carbohydrate, reduced fecundity, and reduced tolerance of heat and cold. However, the ablated flies show an extension of median and maximal lifespan and increased resistance to oxidative stress and starvation.

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                28 December 2015
                December 2015
                : 11
                : 12
                : e1005683
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
                [2 ]Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
                University of California Davis, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: EJR. Performed the experiments: EJR MSN SSG. Analyzed the data: EJR. Contributed reagents/materials/analysis tools: EJR SSG. Wrote the paper: EJR SSG.

                Article
                PGENETICS-D-15-00832
                10.1371/journal.pgen.1005683
                4692505
                26710087
                2c21fbc6-0b4f-4abe-8d12-8490b84d7ebe
                © 2015 Rideout et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 3 April 2015
                : 28 October 2015
                Page count
                Figures: 4, Tables: 0, Pages: 23
                Funding
                This work was supported by operating grants from the Canadian Institute for Health Research (MOP-86622) and Alberta Cancer Board to SSG. EJR was supported by postdoctoral fellowships from Alberta Innovates-Health Solutions and the Alberta Cancer Foundation, and by start-up funds from the Dept. Cellular and Physiological Sciences at The University of British Columbia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Genetics
                Genetics

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