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1.
Curr Biol ; 27(11): 1652-1659.e4, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28528906

RESUMO

Coordination of growth between individual organs and the whole body is essential during development to produce adults with appropriate size and proportions [1, 2]. How local organ-intrinsic signals and nutrient-dependent systemic factors are integrated to generate correctly proportioned organisms under different environmental conditions is poorly understood. In Drosophila, Hippo/Warts signaling functions intrinsically to regulate tissue growth and organ size [3, 4], whereas systemic growth is controlled via antagonistic interactions of the steroid hormone ecdysone and nutrient-dependent insulin/insulin-like growth factor (IGF) (insulin) signaling [2, 5]. The interplay between insulin and ecdysone signaling regulates systemic growth and controls organismal size. Here, we show that Warts (Wts; LATS1/2) signaling regulates systemic growth in Drosophila by activating basal ecdysone production, which negatively regulates body growth. Further, we provide evidence that Wts mediates effects of insulin and the neuropeptide prothoracicotropic hormone (PTTH) on regulation of ecdysone production through Yorkie (Yki; YAP/TAZ) and the microRNA bantam (ban). Thus, Wts couples insulin signaling with ecdysone production to adjust systemic growth in response to nutritional conditions during development. Inhibition of Wts activity in the ecdysone-producing cells non-autonomously slows the growth of the developing imaginal-disc tissues while simultaneously leading to overgrowth of the animal. This indicates that ecdysone, while restricting overall body growth, is limiting for growth of certain organs. Our data show that, in addition to its well-known intrinsic role in restricting organ growth, Wts/Yki/ban signaling also controls growth systemically by regulating ecdysone production, a mechanism that we propose controls growth between tissues and organismal size in response to nutrient availability.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Ecdisona/metabolismo , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Tamanho do Órgão/fisiologia , Proteínas Quinases/metabolismo , Transativadores/metabolismo , Animais , Feminino , Hormônios de Inseto/metabolismo , Insulina/metabolismo , Larva/fisiologia , Masculino , Pupa/fisiologia , Transdução de Sinais/fisiologia , Proteínas de Sinalização YAP
2.
Dev Cell ; 37(6): 558-70, 2016 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-27326933

RESUMO

Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms are regulated by TOR and feedback signaling that couples steroidogenesis with growth and ensures proper maturation timing. These results reveal genes regulating steroidogenesis during development that likely modulate disease mechanisms.


Assuntos
Drosophila melanogaster/genética , Desenvolvimento Embrionário/genética , Testes Genéticos , Genoma de Inseto , Hormônios/biossíntese , Esteroides/biossíntese , Acetiltransferases/metabolismo , Animais , Autofagia/genética , Transporte Biológico/genética , Colesterol/metabolismo , Proteínas de Drosophila/metabolismo , Ecdisona/metabolismo , Elongases de Ácidos Graxos , Metabolismo dos Lipídeos/genética , Fenótipo , Interferência de RNA , Transdução de Sinais/genética , Esfingolipídeos/metabolismo , Fatores de Tempo
3.
PLoS Genet ; 10(6): e1004343, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24945799

RESUMO

Specialized endocrine cells produce and release steroid hormones that govern development, metabolism and reproduction. In order to synthesize steroids, all the genes in the biosynthetic pathway must be coordinately turned on in steroidogenic cells. In Drosophila, the steroid producing endocrine cells are located in the prothoracic gland (PG) that releases the steroid hormone ecdysone. The transcriptional regulatory network that specifies the unique PG specific expression pattern of the ecdysone biosynthetic genes remains unknown. Here, we show that two transcription factors, the POU-domain Ventral veins lacking (Vvl) and the nuclear receptor Knirps (Kni), have essential roles in the PG during larval development. Vvl is highly expressed in the PG during embryogenesis and is enriched in the gland during larval development, suggesting that Vvl might function as a master transcriptional regulator in this tissue. Vvl and Kni bind to PG specific cis-regulatory elements that are required for expression of the ecdysone biosynthetic genes. Knock down of either vvl or kni in the PG results in a larval developmental arrest due to failure in ecdysone production. Furthermore, Vvl and Kni are also required for maintenance of TOR/S6K and prothoracicotropic hormone (PTTH) signaling in the PG, two major pathways that control ecdysone biosynthesis and PG cell growth. We also show that the transcriptional regulator, Molting defective (Mld), controls early biosynthetic pathway steps. Our data show that Vvl and Kni directly regulate ecdysone biosynthesis by transcriptional control of biosynthetic gene expression and indirectly by affecting PTTH and TOR/S6K signaling. This provides new insight into the regulatory network of transcription factors involved in the coordinated regulation of steroidogenic cell specific transcription, and identifies a new function of Vvl and Knirps in endocrine cells during post-embryonic development.


Assuntos
Proteínas de Drosophila/metabolismo , Ecdisona/biossíntese , Hormônios de Inseto/biossíntese , Proteínas Nucleares/metabolismo , Fatores do Domínio POU/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/biossíntese , Animais , Sítios de Ligação , Transporte Biológico/genética , Colesterol/metabolismo , Proteínas de Ligação a DNA , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Ecdisona/genética , Ecdisona/metabolismo , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hormônios de Inseto/metabolismo , Proteínas de Membrana/biossíntese , Fatores do Domínio POU/biossíntese , Fatores do Domínio POU/genética , Interferência de RNA , RNA Interferente Pequeno , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Serina-Treonina Quinases TOR/biossíntese , Transcrição Gênica
4.
Development ; 140(23): 4730-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24173800

RESUMO

Steroid hormones trigger the onset of sexual maturation in animals by initiating genetic response programs that are determined by steroid pulse frequency, amplitude and duration. Although steroid pulses coordinate growth and timing of maturation during development, the mechanisms generating these pulses are not known. Here we show that the ecdysone steroid pulse that drives the juvenile-adult transition in Drosophila is determined by feedback circuits in the prothoracic gland (PG), the major steroid-producing tissue of insect larvae. These circuits coordinate the activation and repression of hormone synthesis, the two key parameters determining pulse shape (amplitude and duration). We show that ecdysone has a positive-feedback effect on the PG, rapidly amplifying its own synthesis to trigger pupariation as the onset of maturation. During the prepupal stage, a negative-feedback signal ensures the decline in ecdysone levels required to produce a temporal steroid pulse that drives developmental progression to adulthood. The feedback circuits rely on a developmental switch in the expression of Broad isoforms that transcriptionally activate or silence components in the ecdysone biosynthetic pathway. Remarkably, our study shows that the same well-defined genetic program that stimulates a systemic downstream response to ecdysone is also utilized upstream to set the duration and amplitude of the ecdysone pulse. Activation of this switch-like mechanism ensures a rapid, self-limiting PG response that functions in producing steroid oscillations that can guide the decision to terminate growth and promote maturation.


Assuntos
Drosophila melanogaster/embriologia , Ecdisona/metabolismo , Hormônios de Inseto/metabolismo , Maturidade Sexual/genética , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Ecdisona/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Larva/crescimento & desenvolvimento , Larva/metabolismo , Metamorfose Biológica/genética , Regiões Promotoras Genéticas , Transdução de Sinais
5.
Curr Top Dev Biol ; 105: 37-67, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23962838

RESUMO

In animals, developmental timing of sexual maturation is tightly linked to nutrition and growth. Maturation only occurs once the juvenile has acquired sufficient nutrients and completed enough growth to produce a reproductively mature adult with a genetically predefined body size. Animals therefore adjust the duration of juvenile development to the dietary conditions. When nutrients are scarce the juvenile growth phase is extended to compensate for slow growth. Conversely, development is accelerated in nutrient rich environments where animals rapidly reach their genetic target size. To achieve such flexibility, nutrient-dependent growth regulators must feed into the endocrine system that controls the timing of maturation. Work on the fruit fly Drosophila has revealed a central role of secreted signal molecules with similarity to the conserved insulin-like growth factors (IGFs) in the decision making process. These molecules are involved in checkpoints that allow the endocrine system to decide whether to release the steroid hormone, ecdysone, that triggers maturation or extent development, depending on nutrient levels and growth status. Importantly, different dietary components influence timing of maturation in Drosophila, with proteins having the greatest impact; fat and sugar play a minor role, at least within the limits of what can be considered a balanced diet. Remarkably, excess dietary sugar concentrations that mimic physiological conditions associated with diabetes, negatively affect growth and delays maturation. Altogether, this shows that the source of energy in the diet is important for timing and may provide a paradigm for understanding the emerging links between diet, obesity and diabetes, and the onset of puberty. Here, we provide an overview of the system underlying developmental timing of maturation in Drosophila and review recent success in understanding its coupling to nutrition and growth.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Proteínas Alimentares/farmacologia , Sacarose Alimentar/farmacologia , Metabolismo Energético/fisiologia , Crescimento e Desenvolvimento/fisiologia , Maturidade Sexual/fisiologia , Transdução de Sinais/fisiologia , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Crescimento e Desenvolvimento/efeitos dos fármacos , Insulina/metabolismo , Modelos Biológicos , Maturidade Sexual/efeitos dos fármacos , Especificidade da Espécie , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo
6.
PLoS One ; 8(2): e55131, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23383307

RESUMO

Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.


Assuntos
Drosophila melanogaster/metabolismo , Ecdisona/biossíntese , Glândulas Exócrinas/metabolismo , Hormônios de Inseto/metabolismo , Tribolium/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/genética , Ecdisona/genética , Ecdisterona/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Hibridização In Situ , Masculino , Microscopia de Fluorescência , Ovário/metabolismo , Reação em Cadeia da Polimerase , Interferência de RNA
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