Browsing by Author "Koyama, Takashi"
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- Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timingPublication . Garelli, Andres; Heredia, Fabiana; Casimiro, Andreia P.; Macedo, Andre; Nunes, Catarina; Garcez, Marcia; Dias, Angela R. Mantas; Volonte, Yanel A.; Uhlmann, Thomas; Caparros, Esther; Koyama, Takashi; Gontijo, Alisson M.How different organs in the body sense growth perturbations in distant tissues to coordinate their size during development is poorly understood. Here we mutate an invertebrate orphan relaxin receptor gene, the Drosophila Leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), and find body asymmetries similar to those found in insulin-like peptide 8 (dilp8) mutants, which fail to coordinate growth with developmental timing. Indeed, mutation or RNA intereference (RNAi) against Lgr3 suppresses the delay in pupariation induced by imaginal disc growth perturbation or ectopic Dilp8 expression. By tagging endogenous Lgr3 and performing cell type-specific RNAi, we map this Lgr3 activity to a new subset of CNS neurons, four of which are a pair of bilateral pars intercerebralis Lgr3-positive (PIL) neurons that respond specifically to ectopic Dilp8 by increasing cAMP-dependent signalling. Our work sheds new light on the function and evolution of relaxin receptors and reveals a novel neuroendocrine circuit responsive to growth aberrations.
- Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size RegulationPublication . Koyama, Takashi; Mirth, Christen K.In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size.
- Mechanisms regulating nutrition-dependent developmental plasticity through organ-specific effects in insectsPublication . Koyama, Takashi; Mendes, Cláudia C.; Mirth, Christen K.Nutrition, via the insulin/insulin-like growth factor (IIS)/Target of Rapamycin (TOR) signaling pathway, can provide a strong molding force for determining animal size and shape. For instance, nutrition induces a disproportionate increase in the size of male horns in dung and rhinoceros beetles, or mandibles in staghorn or horned flour beetles, relative to body size. In these species, well-fed male larvae produce adults with greatly enlarged horns or mandibles, whereas males that are starved or poorly fed as larvae bear much more modest appendages. Changes in IIS/TOR signaling plays a key role in appendage development by regulating growth in the horn and mandible primordia. In contrast, changes in the IIS/TOR pathway produce minimal effects on the size of other adult structures, such as the male genitalia in fruit flies and dung beetles. The horn, mandible and genitalia illustrate that although all tissues are exposed to the same hormonal environment within the larval body, the extent to which insulin can induce growth is organ specific. In addition, the IIS/TOR pathway affects body size and shape by controlling production of metamorphic hormones important for regulating developmental timing, like the steroid molting hormone ecdysone and sesquiterpenoid hormone juvenile hormone. In this review, we discuss recent results from Drosophila and other insects that highlight mechanisms allowing tissues to differ in their sensitivity to IIS/TOR and the potential consequences of these differences on body size and shape.
- Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesisPublication . Koyama, Takashi; Rodrigues, Marisa A; Athanasiadis, Alekos; Shingleton, Alexander W; Mirth, Christen KDespite their fundamental importance for body size regulation, the mechanisms that stop growth are poorly understood. In Drosophila melanogaster, growth ceases in response to a peak of the molting hormone ecdysone that coincides with a nutrition-dependent checkpoint, critical weight. Previous studies indicate that insulin/insulin-like growth factor signaling (IIS)/Target of Rapamycin (TOR) signaling in the prothoracic glands (PGs) regulates ecdysone biosynthesis and critical weight. Here we elucidate a mechanism through which this occurs. We show that Forkhead Box class O (FoxO), a negative regulator of IIS/TOR, directly interacts with Ultraspiracle (Usp), part of the ecdysone receptor. While overexpressing FoxO in the PGs delays ecdysone biosynthesis and critical weight, disrupting FoxO-Usp binding reduces these delays. Further, feeding ecdysone to larvae eliminates the effects of critical weight. Thus, nutrition controls ecdysone biosynthesis partially via FoxO-Usp prior to critical weight, ensuring that growth only stops once larvae have achieved a target nutritional status.
- Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesisPublication . Koyama, Takashi; Rodrigues, Marisa A; Athanasiadis, Alekos; Shingleton, Alexander W; Mirth, Christen KDespite their fundamental importance for body size regulation, the mechanisms that stop growth are poorly understood. In Drosophila melanogaster, growth ceases in response to a peak of the molting hormone ecdysone that coincides with a nutrition-dependent checkpoint, critical weight. Previous studies indicate that insulin/insulin-like growth factor signaling (IIS)/Target of Rapamycin (TOR) signaling in the prothoracic glands (PGs) regulates ecdysone biosynthesis and critical weight. Here we elucidate a mechanism through which this occurs. We show that Forkhead Box class O (FoxO), a negative regulator of IIS/TOR, directly interacts with Ultraspiracle (Usp), part of the ecdysone receptor. While overexpressing FoxO in the PGs delays ecdysone biosynthesis and critical weight, disrupting FoxO-Usp binding reduces these delays. Further, feeding ecdysone to larvae eliminates the effects of critical weight. Thus, nutrition controls ecdysone biosynthesis partially via FoxO-Usp prior to critical weight, ensuring that growth only stops once larvae have achieved a target nutritional status.
- The POU Factor Ventral Veins Lacking/Drifter Directs the Timing of Metamorphosis through Ecdysteroid and Juvenile Hormone SignalingPublication . Cheng, CeCe; Ko, Amy; Chaieb, Leila; Koyama, Takashi; Sarwar, Prioty; Mirth, Christen K.; Smith, Wendy A.; Suzuki, YuichiroAlthough endocrine changes are known to modulate the timing of major developmental transitions, the genetic mechanisms underlying these changes remain poorly understood. In insects, two developmental hormones, juvenile hormone (JH) and ecdysteroids, are coordinated with each other to induce developmental changes associated with metamorphosis. However, the regulation underlying the coordination of JH and ecdysteroid synthesis remains elusive. Here, we examined the function of a homolog of the vertebrate POU domain protein, Ventral veins lacking (Vvl)/Drifter, in regulating both of these hormonal pathways in the red flour beetle, Tribolium castaneum (Tenebrionidae). RNA interference-mediated silencing of vvl expression led to both precocious metamorphosis and inhibition of molting in the larva. Ectopic application of a JH analog on vvl knockdown larvae delayed the onset of metamorphosis and led to a prolonged larval stage, indicating that Vvl acts upstream of JH signaling. Accordingly, vvl knockdown also reduced the expression of a JH biosynthesis gene, JH acid methyltransferase 3 (jhamt3). In addition, ecdysone titer and the expression of the ecdysone response gene, hormone receptor 3 (HR3), were reduced in vvl knockdown larvae. The expression of the ecdysone biosynthesis gene phantom (phm) and spook (spo) were reduced in vvl knockdown larvae in the anterior and posterior halves, respectively, indicating that Vvl might influence ecdysone biosynthesis in both the prothoracic gland and additional endocrine sources. Injection of 20-hydroxyecdysone (20E) into vvl knockdown larvae could restore the expression of HR3 although molting was never restored. These findings suggest that Vvl coordinates both JH and ecdysteroid biosynthesis as well as molting behavior to influence molting and the timing of metamorphosis. Thus, in both vertebrates and insects, POU factors modulate the production of major neuroendocrine regulators during sexual maturation.
- The role of juvenile hormone and insulin/TOR signaling in the growth of Manduca sextaPublication . Hatem, Nicole E.; Wang, Zhou; Nave, Keelin B.; Koyama, Takashi; Suzuki, YuichiroIn many insect species, fitness trade-offs exist between maximizing body size and developmental speed. Understanding how various species evolve different life history strategies requires knowledge of the physiological mechanisms underlying the regulation of body size and developmental timing. Here the roles of juvenile hormone (JH) and insulin/target of rapamycin (TOR) signaling in the regulation of the final body size were examined in the tobacco hornworm, Manduca sexta.