A temporal allocation of amino acid resources ensures fitness and body allometry in Drosophila.

Organisms have evolved strategies to store resources and overcome periods of low or no nutrient access, including transient shortages or longer non-feeding developmental transitions. Holometabolous insects like Drosophila represent an attractive model to study resource allocation during development because they alternate feeding and non-feeding periods. Amino acids are essential components for tissue growth and renewal, but the strategies used for their storage remain largely unexplored. Here, we characterize the molecular mechanisms for the temporal production, accumulation, and use of specific storage proteins called hexamerins, and demonstrate their role in ensuring tissue formation and adult fitness. Moreover, we show that preventing hexamerin stores enhances the growth of early-developing organs while compromising the emergence of late-forming ones, consequently altering body allometry.

An integrative approach to dietary balance across the life course.

Animals require specific blends of nutrients that vary across the life course and with circumstances, e.g., health and activity levels. Underpinning and complicating these requirements is that individual traits may be optimized on different dietary compositions leading to nutrition-mediated trade-offs among outcomes. Additionally, the food environment may constrain which nutrient mixtures are achievable. Natural selection has equipped animals for solving such multi-dimensional, dynamic challenges of nutrition, but little is understood about the details and their theoretical and practical implications. We present an integrative framework, nutritional geometry, which models complex nutritional interactions in the context of multiple nutrients and across levels of biological organization (e.g., cellular, individual, and population) and levels of analysis (e.g., mechanistic, developmental, ecological, and evolutionary). The framework is generalizable across different situations and taxa. We illustrate this using examples spanning insects to primates and settings (laboratory, and the wild), and demonstrate its relevance for human health.

Non-visual cues and indirect strategies that enable discrimination of asymmetric mates.

The postulates of developmental instability-sexual selection hypothesis is intensely debated among evolutionary biologists, wherein despite a large amount of empirical data, evidence for or against it has been largely inconclusive. A key assumption of this hypothesis is that animals assess symmetry in potential mates as an indicator of genetic quality (developmental stability), and consequently use this information to discriminate against those with higher asymmetries while choosing mates. However, the perceptional basis that must underlie such discriminatory behavior (is symmetry a signal or is symmetry signaled) is not clearly defined. It is also argued that since asymmetry levels in natural populations are very low, the low signal-to-noise ratio would make accurate assessment of symmetry both difficult and costly. Rather than attempting to validate this hypothesis or even as to whether animals assess mate symmetry, this review simply aims to examine the plausibility that animals perceive symmetry (directly or indirectly) and consequently discriminate against asymmetric mates in response to perceived irregularities during courtship. For this, we review mate choice and courtship literature to identify potential sensory cues that might advertise asymmetry or lead to discrimination of asymmetric individuals. Although signaling associated with mate choice is commonly multimodal, previous studies on asymmetry have mainly focused on visual perception. In the light of a recent study (Vijendravarma et al., 2022, Proceedings of the National Academy of Sciences of the United States of America, 119, e2116136119), this review attempts to balance this bias by emphasizing on non-visual perception of asymmetry. In conclusion, we discuss the methodological challenges associated with testing the role of multimodal cues in detecting mate asymmetry, and highlight the importance of considering ecological, behavioral, and evolutionary aspects of animals while interpreting empirical data that test such hypothesis.

A local insulin reservoir in Drosophila alpha cell homologs ensures developmental progression under nutrient shortage.

Insulin/insulin-like growth factor (IGF) signaling (IIS) controls many aspects of development and physiology. In Drosophila, a conserved family of insulin-like peptides called Dilps is produced by brain neurosecretory cells, and it regulates organismal growth and developmental timing. To accomplish these systemic functions, the Dilps are secreted into the general circulation, and they signal to peripheral tissues in an endocrine fashion. Here, we describe the local uptake and storage of Dilps in the corpora cardiaca (CC), an endocrine organ composed of alpha cell homologs known to produce the glucagon-like adipokinetic hormone (AKH). We show that Dilp uptake by the CC relies on the expression of an IGF-binding protein called ImpL2. Following their uptake, immunogold staining demonstrates that Dilps are co-packaged with AKH in dense-core vesicles for secretion. In response to nutrient shortage, this specific Dilp reservoir is released and activates IIS in a paracrine manner in the prothoracic gland. This stimulates the production of the steroid hormone ecdysone and initiates entry into pupal development. We therefore uncover a sparing mechanism whereby insulin stores in CC serve to locally activate IIS and the production of ecdysone in the PG, accelerating developmental progression in adverse food conditions.

Drosophila females have an acoustic preference for symmetric males.

SignificanceTheoretically, symmetry in bilateral animals is subject to sexual selection, since it can serve as a proxy for genetic quality of competing mates during mate choice. Here, we report female preference for symmetric males in Drosophila, using a mate-choice paradigm where males with environmentally or genetically induced wing asymmetry were competed. Analysis of courtship songs revealed that males with asymmetric wings produced songs with asymmetric features that served as acoustic cues, facilitating this female preference. Females experimentally evolved in the absence of mate choice lost this preference for symmetry, suggesting that it is maintained by sexual selection.

An Oatp transporter-mediated steroid sink promotes tumor-induced cachexia in Drosophila.

Cancer cachexia is associated with many types of tumors and is characterized by a combination of anorexia, loss of body weight, catabolic alterations, and systemic inflammation. We developed a tumor model in Drosophila larvae that causies cachexia-like syndrome, and we found that cachectic larvae show reduced levels of the circulating steroid ecdysone (Ec). Artificially importing Ec in the tumor through the use of the EcI/Oatp74D importer aggravated cachexia, whereas feeding animals with Ec rescued cachectic defects. This suggests that a steroid sink induced by the tumor promotes catabolic alterations in healthy tissues. We found that Oatp33Eb, a member of the Oatp transporter family, is specifically induced in tumors promoting cachexia. The overexpression of Oatp33Eb in noncachectic tumors induced cachexia, whereas its inhibition in cachectic tumors restored circulating Ec and reversed cachectic alterations. Oatp transporters are induced in several types of hormone-dependent tumors, and this result suggests that a similar sink effect could modify hormonal balance in cachectic cancer patients.

Brain adiponectin signaling controls peripheral insulin response in Drosophila.

The brain plays a key role in energy homeostasis, detecting nutrients, metabolites and circulating hormones from peripheral organs and integrating this information to control food intake and energy expenditure. Here, we show that a group of neurons in the Drosophila larval brain expresses the adiponectin receptor (AdipoR) and controls systemic growth and metabolism through insulin signaling. We identify glucose-regulated protein 78 (Grp78) as a circulating antagonist of AdipoR function produced by fat cells in response to dietary sugar. We further show that central AdipoR signaling inhibits peripheral Juvenile Hormone (JH) response, promoting insulin signaling. In conclusion, we identify a neuroendocrine axis whereby AdipoR-positive neurons control systemic insulin response.

Sizes, proportions and environment.

The sizes of living organisms range over twenty orders of magnitude. Within the same species, the size of individuals also varies according to the environmental conditions to which they are subjected. From the studies conducted on organisms as diverse as the drosophila, the salamander or the mouse, laws and conserved mechanisms emerge that shed light on the fundamental aspects of growth, but also on more medical issues such as tissue regeneration, metabolic homeostasis and cancer.

Les tailles des organismes vivants s'échelonnent sur plus de vingt ordres de grandeur. Au sein d'une même espèce, la taille des individus varie également en fonction des conditions environnementales auxquelles ils sont soumis. A partir des études menées sur des organismes aussi divers que la drosophile, la salamandre ou la souris, émergent des lois et des mécanismes conservés qui nous éclairent sur les aspects fondamentaux de la croissance, mais aussi sur des problématiques à portée plus médicale telles que la régénération tissulaire, l'homéostasie métabolique et le cancer.

What determines organ size during development and regeneration?

The sizes of living organisms span over 20 orders of magnitude or so. This daunting observation could intimidate researchers aiming to understand the general mechanisms controlling growth. However, recent progress suggests the existence of principles common to organisms as diverse as fruit flies, mice and humans. As we review here, these studies have provided insights into both autonomous and non-autonomous mechanisms controlling organ growth as well as some of the principles underlying growth coordination between organs and across bilaterally symmetrical organisms. This research tackles several aspects of developmental biology and integrates inputs from physics, mathematical modelling and evolutionary biology. Although many open questions remain, this work also helps to shed light on medically related conditions such as tissue and limb regeneration, as well as metabolic homeostasis and cancer.

Hyperinsulinemia Drives Epithelial Tumorigenesis by Abrogating Cell Competition.

Metabolic diseases such as type 2 diabetes are associated with increased cancer incidence. Here, we show that hyperinsulinemia promotes epithelial tumorigenesis by abrogating cell competition. In Drosophila eye imaginal epithelium, oncogenic scribble (scrib) mutant cells are eliminated by cell competition when surrounded by wild-type cells. Through a genetic screen, we find that flies heterozygous for the insulin receptor substrate chico allow scrib cells to evade cell competition and develop into tumors. Intriguingly, chico is required in the brain's insulin-producing cells (IPCs) to execute cell competition remotely. Mechanistically, chico downregulation in IPCs causes hyperinsulinemia by upregulating a Drosophila insulin Dilp2, which activates insulin-mTOR signaling and thus boosts protein synthesis in scrib cells. A diet-induced increase in insulin levels also triggers scrib tumorigenesis, and pharmacological repression of protein synthesis prevents hyperinsulinemia-induced scrib overgrowth. Our findings provide an in vivo mechanistic link between metabolic disease and cancer risk via systemic regulation of cell competition.

Inter-Organ Growth Coordination Is Mediated by the Xrp1-Dilp8 Axis in Drosophila.

How organs scale with other body parts is not mechanistically understood. We have addressed this question using the Drosophila imaginal disc model. When the growth of one disc domain is perturbed, other parts of the disc and other discs slow down their growth, maintaining proper inter-disc and intra-disc proportions. We show here that the relaxin-like Dilp8 is required for this inter-organ coordination. Our work also reveals that the stress-response transcription factor Xrp1 plays a key role upstream of dilp8 in linking organ growth status with the systemic growth response. In addition, we show that the small ribosomal subunit protein RpS12 is required to trigger Xrp1-dependent non-autonomous response. Our work demonstrates that RpS12, Xrp1, and Dilp8 form an independent regulatory module that ensures intra- and inter-organ growth coordination during development.

AstA Signaling Functions as an Evolutionary Conserved Mechanism Timing Juvenile to Adult Transition.

The onset of sexual maturation is the result of a hormonal cascade peaking with the production of steroid hormones. In animals undergoing a program of determinate growth, sexual maturation also coincides with the attainment of adult size. The exact signals that time the onset of maturation and the mechanisms coupling growth and maturation remain elusive. Here, we show that the Drosophila neuropeptide AstA and its receptor AstAR1 act as a brain trigger for maturation and juvenile growth. We first identified AstAR1 in an RNAi-based genetic screen as a key regulator of sexual maturation. Its specific knockdown in prothoracicotropic hormone (PTTH)-producing neurons delays the onset of maturation by impairing PTTH secretion. In addition to its role in PTTH neurons, AstAR1 is required in the brain insulin-producing cells (IPCs) to promote insulin secretion and systemic growth. AstAR1 function is mediated by the AstA neuropeptide that is expressed in two bilateral neurons contacting the PTTH neurons and the IPCs. Silencing brain AstA expression delays the onset of maturation, therefore extending the growth period. However, no pupal overgrowth is observed, indicating that, in these conditions, the growth-promoting function of AstAR1 is also impaired. These data suggest that AstA/AstAR1 acts to coordinate juvenile growth with maturation. Interesting, AstA/AstAR1 is homologous to KISS/GPR54, a ligand-receptor signal required for human puberty, suggesting that an evolutionary conserved neural circuitry controls the onset of maturation.

Control of basal autophagy rate by vacuolar peduncle.

Basal autophagy is as a compressive catabolic mechanism engaged in the breakdown of damaged macromolecules and organelles leading to the recycling of elementary nutrients. Thought essential to cellular refreshing, little is known about the origin of a constitutional rate of basal autophagy. Here, we found that loss of Drosophila vacuolar peduncle (vap), a presumed GAP enzyme, is associated with enhanced basal autophagy rate and physiological alterations resulting in a wasteful cell energy balance, a hallmark of overactive autophagy. By contrast, starvation-induced autophagy was disrupted in vap mutant conditions, leading to a block of maturation into autolysosomes. This phenotype stem for exacerbated biogenesis of PI(3)P-dependent endomembranes, including autophagosome membranes and ectopic fusions of vesicles. These findings shed new light on the neurodegenerative phenotype found associated to mutant vap adult brains in a former study. A partner of Vap, Sprint (Spri), acting as an endocytic GEF for Rab5, had the converse effect of leading to a reduction in PI(3)P-dependent endomembrane formation in mutants. Spri was conditional to normal basal autophagy and instrumental to the starvation-sensitivity phenotype specific of vap. Rab5 activity itself was essential for PI(3)P and for pre-autophagosome structures formation. We propose that Vap/Spri complexes promote a cell surface-derived flow of endocytic Rab5-containing vesicles, the traffic of which is crucial for the implementation of a basal autophagy rate.

An EGF-Responsive Neural Circuit Couples Insulin Secretion with Nutrition in Drosophila.

Developing organisms use fine-tuning mechanisms to adjust body growth to ever-changing nutritional conditions. In Drosophila, the secretory activity of insulin-producing cells (IPCs) is central to couple systemic growth with amino acids availability. Here, we identify a subpopulation of inhibitory neurons contacting the IPCs (IPC-connecting neurons or ICNs) that play a key role in this coupling. We show that ICNs respond to growth-blocking peptides (GBPs), a family of fat-body-derived signals produced upon availability of dietary amino acids. We demonstrate that GBPs are atypical ligands for the fly EGF receptor (EGFR). Upon activation of EGFR by adipose GBPs, ICN-mediated inhibition of IPC function is relieved, allowing insulin secretion. Our study reveals an unexpected role for EGF-like metabolic hormones and EGFR signaling as critical modulators of neural activity, coupling insulin secretion to the nutritional status.

Prothoracicotropic hormone modulates environmental adaptive plasticity through the control of developmental timing.

Adult size and fitness are controlled by a combination of genetics and environmental cues. In Drosophila, growth is confined to the larval phase and final body size is impacted by the duration of this phase, which is under neuroendocrine control. The neuropeptide prothoracicotropic hormone (PTTH) has been proposed to play a central role in controlling the length of the larval phase through regulation of ecdysone production, a steroid hormone that initiates larval molting and metamorphosis. Here, we test this by examining the consequences of null mutations in the Ptth gene for Drosophila development. Loss of Ptth causes several developmental defects, including a delay in developmental timing, increase in critical weight, loss of coordination between body and imaginal disc growth, and reduced adult survival in suboptimal environmental conditions such as nutritional deprivation or high population density. These defects are caused by a decrease in ecdysone production associated with altered transcription of ecdysone biosynthetic genes. Therefore, the PTTH signal contributes to coordination between environmental cues and the developmental program to ensure individual fitness and survival.

[Some insulins to orchestrate growth]. / Des insulines pour orchestrer la croissance.

Body size is an intrinsic property of living organisms that is intimately linked to the developmental program to produce fit individuals with proper proportions. Final size is the result of both genetic determinants and sophisticated mechanisms adapting size to available resources. Even though organs grow according to autonomous programs, some coordination mechanisms ensure that the different body parts adjust their growth with the rest of the body. In Drosophila, Dilp8, a hormone of the Insulin/Relaxin family is a key player in this inter-organs coordination and is required together with its receptor Lgr3 to limit developmental variability. Recently, the transcriptional co-activator Yki (homologue of YAP/TAZ factors in mammals) was shown to regulate dilp8 expression and contribute to the coordination of organ growth in Drosophila.

The Hippo signalling pathway coordinates organ growth and limits developmental variability by controlling dilp8 expression.

Coordination of organ growth during development is required to generate fit individuals with fixed proportions. We recently identified Drosophila Dilp8 as a key hormone in coupling organ growth with animal maturation. In addition, dilp8 mutant flies exhibit elevated fluctuating asymmetry (FA) demonstrating a function for Dilp8 in ensuring developmental stability. The signals regulating Dilp8 activity during normal development are not yet known. Here, we show that the transcriptional co-activators of the Hippo (Hpo) pathway, Yorkie (Yki, YAP/TAZ) and its DNA-binding partner Scalloped (Sd), directly regulate dilp8 expression through a Hpo-responsive element (HRE) in the dilp8 promoter. We further demonstrate that mutation of the HRE by genome-editing results in animals with increased FA, thereby mimicking full dilp8 loss of function. Therefore, our results indicate that growth coordination of organs is connected to their growth status through a feedback loop involving Hpo and Dilp8 signalling pathways.

Drosophila insulin release is triggered by adipose Stunted ligand to brain Methuselah receptor.

Animals adapt their growth rate and body size to available nutrients by a general modulation of insulin-insulin-like growth factor signaling. In Drosophila, dietary amino acids promote the release in the hemolymph of brain insulin-like peptides (Dilps), which in turn activate systemic organ growth. Dilp secretion by insulin-producing cells involves a relay through unknown cytokines produced by fat cells. Here, we identify Methuselah (Mth) as a secretin-incretin receptor subfamily member required in the insulin-producing cells for proper nutrient coupling. We further show, using genetic and ex vivo organ culture experiments, that the Mth ligand Stunted (Sun) is a circulating insulinotropic peptide produced by fat cells. Therefore, Sun and Mth define a new cross-organ circuitry that modulates physiological insulin levels in response to nutrients.

The Drosophila TNF Eiger Is an Adipokine that Acts on Insulin-Producing Cells to Mediate Nutrient Response.

Adaptation of organisms to ever-changing nutritional environments relies on sensor tissues and systemic signals. Identification of these signals would help understand the physiological crosstalk between organs contributing to growth and metabolic homeostasis. Here we show that Eiger, the Drosophila TNF-α, is a metabolic hormone that mediates nutrient response by remotely acting on insulin-producing cells (IPCs). In the condition of nutrient shortage, a metalloprotease of the TNF-α converting enzyme (TACE) family is active in fat body (adipose-like) cells, allowing the cleavage and release of adipose Eiger in the hemolymph. In the brain IPCs, Eiger activates its receptor Grindelwald, leading to JNK-dependent inhibition of insulin production. Therefore, we have identified a humoral connexion between the fat body and the brain insulin-producing cells relying on TNF-α that mediates adaptive response to nutrient deprivation.