Sensing of amino acids in a dopaminergic circuitry promotes rejection of an incomplete diet in Drosophila.

The brain is the central organizer of food intake, matching the quality and quantity of the food sources with organismal needs. To ensure appropriate amino acid balance, many species reject a diet lacking one or several essential amino acids (EAAs) and seek out a better food source. Here, we show that, in Drosophila larvae, this behavior relies on innate sensing of amino acids in dopaminergic (DA) neurons of the brain. We demonstrate that the amino acid sensor GCN2 acts upstream of GABA signaling in DA neurons to promote avoidance of the EAA-deficient diet. Using real-time calcium imaging in larval brains, we show that amino acid imbalance induces a rapid and reversible activation of three DA neurons that are necessary and sufficient for food rejection. Taken together, these data identify a central amino-acid-sensing mechanism operating in specific DA neurons and controlling food intake.

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.

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.

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.

The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth.

Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. Grnd also promotes the invasiveness of Ras(V12)/scrib(-/-) tumours through Egr-dependent Matrix metalloprotease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.

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.

Drosophila ALS regulates growth and metabolism through functional interaction with insulin-like peptides.

In metazoans, factors of the insulin family control growth, metabolism, longevity, and fertility in response to environmental cues. In Drosophila, a family of seven insulin-like peptides, called Dilps, activate a common insulin receptor. Some Dilp peptides carry both metabolic and growth functions, raising the possibility that various binding partners specify their functions. Here we identify dALS, the fly ortholog of the vertebrate insulin-like growth factor (IGF)-binding protein acid-labile subunit (ALS), as a Dilp partner that forms a circulating trimeric complex with one molecule of Dilp and one molecule of Imp-L2, an IgG-family molecule distantly related to mammalian IGF-binding proteins (IGFBPs). We further show that dALS antagonizes Dilp function to control animal growth as well as carbohydrate and fat metabolism. These results lead us to propose an evolutionary perspective in which ALS function appeared prior to the separation between metabolic and growth effects that are associated with vertebrate insulin and IGFs.

Drosophila and the genetics of the internal milieu.

'Homeostasis', from the Greek words for 'same' and 'steady', refers to ways in which the body acts to maintain a stable internal environment despite perturbations. Recent studies in Drosophila exemplify the conservation of regulatory mechanisms involved in metabolic homeostasis. These new findings underscore the use of Drosophila as a model for the study of various human disorders.

Fly foie gras: modeling fatty liver in Drosophila.

Lipids provide an essential source of metabolites and energy in normal development as well as during periods of food deprivation. A recent study in Drosophila (Gutierrez et al., 2007) reveals a novel role in regulating lipid metabolism for specialized cells called oenocytes that present striking functional similarities to mammalian hepatocytes.

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.

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.

The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila.

Tissue growth during animal development is tightly controlled so that the organism can develop harmoniously. The salvador (sav) gene, which encodes a scaffold protein, has been shown to restrict cell number by coordinating cell-cycle exit and apoptosis during Drosophila development. Here we identify Hippo (Hpo), the Drosophila orthologue of the mammalian MST1 and MST2 serine/threonine kinases, as a partner of Sav. Loss of hpo function leads to sav-like phenotypes, whereas gain of hpo function results in the opposite phenotype. Whereas Sav and Hpo normally restrict cellular quantities of the Drosophila inhibitor of apoptosis protein DIAP1, overexpression of Hpo destabilizes DIAP1 in cell culture. We show that DIAP1 is phosphorylated in a Hpo-dependent manner in S2 cells and that Hpo can phosphorylate DIAP1 in vitro. Thus, Hpo may promote apoptosis by reducing cellular amounts of DIAP1. In addition, we show that Sav is an unstable protein that is stabilized by Hpo. We propose that Hpo and Sav function together to restrict tissue growth in vivo.

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.

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.

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.

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.

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.