RESUMO
Successful reproduction is dependent on the transfer of male seminal proteins to females upon mating. These proteins arise from secretory tissues in the male reproductive tract, including the prostate and seminal vesicles in mammals and the accessory gland in insects. Although detailed functional studies have provided important insights into the mechanisms by which accessory gland proteins support reproduction, much less is known about the molecular mechanisms that regulate their expression within this tissue. Here we show that the Drosophila HR39 nuclear receptor is required for the proper expression of most genes that encode male accessory gland proteins. Consistent with this role, HR39 mutant males are infertile. In addition, tissue-specific RNAi and genetic rescue experiments indicate that HR39 acts within the accessory glands to regulate gene expression and male fertility. These results provide new directions for characterizing the mammalian orthologs of HR39, the SF-1 and LRH-1 nuclear receptors, both of which are required for glandular secretions and reproduction. In addition, our studies provide a molecular mechanism to explain how the accessory glands can maintain the abundant levels of seminal fluid production required to support fertility.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Infertilidade Masculina/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fertilidade/genética , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Genitália Masculina/metabolismo , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Próstata/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Reprodução/genéticaRESUMO
BACKGROUND: Lipid levels are maintained by balancing lipid uptake, synthesis, and mobilization. Although many studies have focused on the control of lipid synthesis and mobilization, less is known about the regulation of lipid digestion and uptake. RESULTS: Here we show that the Drosophila E78A nuclear receptor plays a central role in intestinal lipid homeostasis through regulation of the CG17192 digestive lipase. E78A mutant adults fail to maintain proper systemic lipid levels following eclosion, with this effect largely restricted to the intestine. Transcriptional profiling by RNA-seq revealed a candidate gene for mediating this effect, encoding the predicted adult intestinal lipase CG17192. Intestine-specific disruption of CG17192 results in reduced lipid levels similar to that seen in E78A mutants. In addition, dietary supplementation with free fatty acids, or intestine-specific expression of either E78A or CG17192, is sufficient to restore lipid levels in E78A mutant adults. CONCLUSION: These studies support the model that E78A is a central regulator of adult lipid homeostasis through its effects on CG17192 expression and lipid digestion. This work also provides new insights into the control of intestinal lipid uptake and demonstrate that nuclear receptors can play an important role in these pathways.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Metabolismo dos Lipídeos , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Sequência de Bases , Gorduras na Dieta , Drosophila/genética , Proteínas de Drosophila/genética , Feminino , Regulação da Expressão Gênica , Homeostase , Intestinos/enzimologia , Lipase/metabolismo , Masculino , Receptores Citoplasmáticos e Nucleares/genéticaRESUMO
OBJECTIVE: A significant portion of the heritable risk for complex metabolic disorders cannot be attributed to classic Mendelian genetic factors. At least some of this missing heritability is thought to be due to the epigenetic influence of parental and grandparental metabolic state on offspring health. Previous work suggests that this transgenerational phenomenon is evolutionarily conserved in Drosophila. These studies, however, have all depended on dietary paradigms to alter parental metabolic state, which can have inconsistent heritable effects on the metabolism of offspring. METHODS: Here we use AKHR null alleles to induce obesity in the parental generation and then score both metabolic parameters and genome-wide transcriptional responses in AKHR heterozygote F1 progeny and genetically wild-type F2 progeny. RESULTS: Unexpectedly, we observe elevated glycogen levels and changes in gene expression in AKHR heterozygotes due to haploinsufficiency at this locus. We also show that genetic manipulation of parental metabolism using AKHR mutations results in significant physiological changes in F2 wild-type offspring of the grandpaternal/maternal lineage. CONCLUSIONS: Our results demonstrate that genetic manipulation of parental metabolism in Drosophila can have an effect on the health of F2 progeny, providing a non-dietary paradigm to better understand the mechanisms behind the transgenerational inheritance of metabolic state.
Assuntos
Impressão Genômica , Obesidade/genética , Animais , Drosophila , Proteínas de Drosophila/genética , Glicogênio/metabolismo , Haploinsuficiência , Receptores de Glucagon/genética , TranscriptomaRESUMO
Many studies have focused on defining the critical transcription factors that specify tissue morphogenesis and differentiation. Our understanding of how these spatial regulators are deployed in the proper temporal order, however, has remained less clear. In this issue of Genes & Development, Uyehara and colleagues (pp. 862-875) provide new insights into the mechanisms by which temporal and spatial regulators are coordinated to control Drosophila wing development during metamorphosis.