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The production of offspring is energetically costly and relies on incompletely understood mechanisms that generate a positive energy balance. In mothers of many species, changes in key energy-associated internal organs are common yet poorly characterised functionally and mechanistically. In this study, we show that, in adult Drosophila females, the midgut is dramatically remodelled to enhance reproductive output. In contrast to extant models, organ remodelling does not occur in response to increased nutrient intake and/or offspring demands, but rather precedes them. With spatially and temporally directed manipulations, we identify juvenile hormone (JH) as an anticipatory endocrine signal released after mating. Acting through intestinal bHLH-PAS domain proteins Methoprene-tolerant (Met) and Germ cell-expressed (Gce), JH signals directly to intestinal progenitors to yield a larger organ, and adjusts gene expression and sterol regulatory element-binding protein (SREBP) activity in enterocytes to support increased lipid metabolism. Our findings identify a metabolically significant paradigm of adult somatic organ remodelling linking hormonal signals, epithelial plasticity, and reproductive output. Producing offspring places extra energy demands on individuals. Female animals—which generally invest more time and resources than the males—need to ensure that sufficient nutrients reach their offspring during pregnancy and lactation. The small intestines of many female animals increase in size during this period, but it is not clear to what extent these changes help to maximise reproduction, or how they are regulated. Reiff, Jacobson, Cognigni, Antonello et al. investigated what happens to the middle section of the gut in female fruit flies after mating. A fly's ‘midgut’ performs a similar role to the small intestine in humans and other mammals. The experiments show that mating increases the numbers of cells in the midgut so that it increases in size. These changes are due to a hormone called ‘juvenile hormone’, which is released after the fly mates. In particular cells of the midgut, juvenile hormone also regulates some genes involved in the metabolism of lipids. If the activity of juvenile hormone is blocked in these cells, the female flies produce fewer eggs. These changes in the midgut still happen in mutant flies that cannot produce eggs and don't increase their food intake after they mate. Therefore, the changes appear to prepare flies for the increased nutritional demands rather than being caused by it. Altogether, these findings reveal that changes in the midgut play an important role in the ability of female fruit flies to reproduce. Similar changes to the gut may also increase reproductive success in humans and other mammals. However, if the changes are maintained after reproduction, it is possible that they may contribute to weight gain and an increased risk of cancer in females after pregnancy.

Gustatory pheromones play an essential role in shaping the behavior of many organisms. However, little is known about the processing of taste pheromones in higher order brain centers. Here, we describe a male-specific gustatory circuit in Drosophila that underlies the detection of the anti-aphrodisiac pheromone (3R,11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol (CH503). Using behavioral analysis, genetic manipulation, and live calcium imaging, we show that Gr68a-expressing neurons on the forelegs of male flies exhibit a sexually dimorphic physiological response to the pheromone and relay information to the central brain via peptidergic neurons. The release of tachykinin from 8 to 10 cells within the subesophageal zone is required for the pheromone-triggered courtship suppression. Taken together, this work describes a neuropeptide-modulated central brain circuit that underlies the programmed behavioral response to a gustatory sex pheromone. These results will allow further examination of the molecular basis by which innate behaviors are modulated by gustatory cues and physiological state. In many species of animals, the male decides to pursue a potential female mate based on how she smells and tastes. Powerful chemical signals known as pheromones control this decision. When a male fruit fly mates with a female fruit fly, he often leaves behind an anti-aphrodisiac pheromone that, when males taste it, deters them from mating with the female. Until recently, however, little was known about how the brain processes information from such taste pheromones. Now, Shankar et al. have investigated this problem in a series of experiments with normal and genetically modified flies. In the first experiment normal male flies were exposed to the chemical on its own, to the chemical on a sample of female skin, and to the chemical on actual female flies. The male flies did not respond to the pheromone on its own, but they did respond to it in the other two scenarios. Next, Shankar et al. used genetic techniques to eliminate individual neurons in the male flies and then observed how the loss of specific neurons influenced the response of the fly to the pheromone. These experiments showed that male flies have a special group of sensory neurons in their legs that detect the chemical and then send an electrical signal to the brain. Shankar et al. then went on to identify a brain circuit consisting of 8–10 neurons that responds to this signal and to show that the release of a neurochemical called Tachykinin is essential in communicating the signal. In a final set of experiments, Shankar et al. introduced two sensors—one in the sensory neurons in the legs, the other in the 8–10 neurons in the brain—that light up when the neurons in that region are close enough to each other to form connections. The results suggest that the sensory neurons in the legs form connections with the 8–10 neurons in the brain. A challenge for the future is to understand how the nervous system combines different social cues and information about the physiological state of the animal, and how this influences the decision to mate.

Some neurodegenerative diseases, like Parkinsons Disease (PD) and Spinocerebellar ataxia 3 (SCA3), are associated with distinct, altered gait and tremor movements that are reflective of the underlying disease etiology. Drosophila melanogaster models of neurodegeneration have illuminated our understanding of the molecular mechanisms of disease. However, it is unknown whether specific gait and tremor dysfunctions also occur in fly disease mutants. To answer this question, we developed a machine-learning image-analysis program, Feature Learning-based LImb segmentation and Tracking (FLLIT), that automatically tracks leg claw positions of freely moving flies recorded on high-speed video, producing a series of gait measurements. Notably, unlike other machine-learning methods, FLLIT generates its own training sets and does not require user-annotated images for learning. Using FLLIT, we carried out high-throughput and high-resolution analysis of gait and tremor features in Drosophila neurodegeneration mutants for the first time. We found that fly models of PD and SCA3 exhibited markedly different walking gait and tremor signatures, which recapitulated characteristics of the respective human diseases. Selective expression of mutant SCA3 in dopaminergic neurons led to a gait signature that more closely resembled those of PD flies. This suggests that the behavioral phenotype depends on the neurons affected rather than the specific nature of the mutation. Different mutations produced tremors in distinct leg pairs, indicating that different motor circuits were affected. Using this approach, fly models can be used to dissect the neurogenetic mechanisms that underlie movement disorders.

Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine-learning method, Feature Learning-based Leg segmentation and Tracking (FLLIT), we previously characterised gait and tremor signatures in a Drosophila model for spinocerebellar ataxia 3 (SCA3) and found them to be analogous to those in human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in, or genetic hypo-activation of, these neurons led to tremor, indicating their important role in adult motor control. RNA-sequencing and functional experiments showed that dysfunction of GABAergic neurons, and not that of other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of ∼30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.

Insects use a spectacular variety of chemical signals to guide their social behaviours. How such chemical diversity arises is a long-standing problem in evolutionary biology. Here we describe the contribution of the fatty acid elongase Bond to both pheromone diversity and male fertility in Drosophila . Genetic manipulation and mass spectrometry analysis reveal that the loss of bond eliminates the male sex pheromone (3 R ,11 Z ,19 Z )-3-acetoxy-11,19-octacosadien-1-ol (CH503). Unexpectedly, silencing bond expression severely suppresses male fertility and the fertility of conspecific rivals. These deficits are rescued on ectopic expression of bond in the male reproductive system. A comparative analysis across six Drosophila species shows that the gain of a novel transcription initiation site is correlated with bond expression in the ejaculatory bulb, a primary site of male pheromone production. Taken together, these results indicate that modification of cis -regulatory elements and subsequent changes in gene expression pattern is one mechanism by which pheromone diversity arises. Insect behaviours are often guided by chemical signals, but little is known about how pheromone diversity evolves. Here the authors show that loss of the gene bond in Drosophila eliminates the sex pheromone CH503, while silencing it reduces the fertility of males and their conspecific rivals.

Many of the lipids found on the cuticles of insects function as pheromones and communicate information about age, sex, and reproductive status. In Drosophila, the composition of the information-rich lipid profile is dynamic and changes over the lifetime of an individual. However, the molecular basis of this change is not well understood. To identify genes that control cuticular lipid production in Drosophila, we performed a RNA interference screen and used Direct Analysis in Real Time and gas chromatography mass spectrometry to quantify changes in the chemical profiles. Twelve putative genes were identified whereby transcriptional silencing led to significant differences in cuticular lipid production. Amongst them, we characterized a gene which we name spidey, and which encodes a putative steroid dehydrogenase that has sex- and age-dependent effects on viability, pheromone production, and oenocyte survival. Transcriptional silencing or overexpression of spidey during embryonic development results in pupal lethality and significant changes in levels of the ecdysone metabolite 20-hydroxyecdysonic acid and 20-hydroxyecdysone. In contrast, inhibiting gene expression only during adulthood resulted in a striking loss of oenocyte cells and a concomitant reduction of cuticular hydrocarbons, desiccation resistance, and lifespan. Oenocyte loss and cuticular lipid levels were partially rescued by 20-hydroxyecdysone supplementation. Taken together, these results identify a novel regulator of pheromone synthesis and reveal that ecdysteroid signaling is essential for the maintenance of cuticular lipids and oenocytes throughout adulthood.

Preovulatory follicle aging is the period between formation and ovulation of a mature follicle. Previous studies had shown that mammalian preovulatory follicle aging is associated with chromosomal abnormalities and developmental defects such as decreased implantation, increased malformation and mortality and lower embryonic weight. Our understanding of the molecular events governing this process has been hampered by the difficulty in accessing them in vivo under natural conditions. We hypothesize that the quality of the mature oocyte is regulated by crosstalk between the oocyte and the somatic microenvironment during extended storage prior to ovulation. By combining temporal profiling and tissue‐specific functional analyzes in Drosophila, we characterize a spatiotemporal crosstalk between the oocyte and the granulosa cells that governs preovulatory follicle aging in vivo. Preovulatory follicle aging is characterized by two distinct phases—early oocyte protective and late degenerative phases. The degenerative phase involves a positive feedback loop between oocyte mitochondrial dysfunction mediated by a mitochondrial‐localized microprotein PIGBOS, and granulosa cell functional decline through a circular RNA circdlg1. Activation of the feedback loop is suppressed by germline Sestrin during the early phase. Our findings highlight that natural preovulatory follicle aging in vivo is governed by a mechanism that represses an oocyte‐degenerative positive feedback loop between oocyte and granulosa cells. Preovulatory follicle aging is characterized by two distinct phases—early oocyte protective and late degenerative phases. The degenerative phase involves a positive feedback loop between oocyte mitochondrial dysfunction mediated by a mitochondrial‐localized microprotein PIGBOS, and granulosa cell functional decline through a circular RNA circdlg1. Activation of the feedback loop is suppressed by germline Sestrin during the early phase. Thus, preovulatory follicle aging is governed by a mechanism that represses an oocyte‐degenerative positive feedback loop between oocyte and granulosa cells.

Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine learning method, FLLIT, we previously characterised gait and tremor signatures in the Drosophila model for Spinocerebellar ataxia 3 (SCA3), and found them to be analogous to human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor, and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in or genetic hypo-activation of these neurons leads to tremor, indicating their important role in adult motor control. RNAseq and functional experiments showed that dysfunction of GABAergic neurons, and not other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of approximately 30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine learning method, FLLIT, we previously characterised gait and tremor signatures in the Drosophila model for Spinocerebellar ataxia 3 (SCA3), and found them to be analogous to human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor, and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in or genetic hypo-activation of these neurons leads to tremor, indicating their important role in adult motor control. RNAseq and functional experiments showed that dysfunction of GABAergic neurons, and not other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of approximately 30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.

Genetic models in Drosophila have made invaluable contributions to our understanding of the molecular mechanisms underlying neurodegeneration. In human patients, some neurodegenerative diseases lead to characteristic movement dysfunctions, such as abnormal gait and tremors. However, it is currently unknown whether similar movement defects occur in the respective fly models, which could be used to model and better understand the pathophysiology of movement disorders. To address this question, we developed a machine-learning image-analysis programme - Feature Learning-based LImb segmentation and Tracking (FLLIT) - that automatically tracks leg claw positions of freely moving flies recorded on high-speed video, generating a series of body and leg movement parameters. Of note, FLLIT requires no user input for learning. We used FLLIT to characterise fly models of Parkinson's Disease (PD) and Spinocerebellar ataxia 3 (SCA3). Between these models, walking gait and tremor characteristics differed markedly, and recapitulated signatures of the respective human diseases. Selective expression of mutant SCA3 in dopaminergic neurons led to phenotypes resembling that of PD flies, suggesting that the behavioural phenotype may depend on the circuits affected, rather than the specific nature of the mutation. Different mutations produced tremors in distinct leg pairs, indicating that different motor circuits are affected. Almost 190,000 video frames were tracked in this study, allowing, for the first time, high-throughput analysis of gait and tremor features in Drosophila mutants. As an efficient assay of mutant gait and tremor features in an important model system, FLLIT will enable the analysis of the neurogenetic mechanisms that underlie movement disorders.