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Researchers are exploring sex differences in experimental models of both development and disease—but are we doing enough? In this collection of Voices, we celebrate researchers who are asking this question and starting to offer mechanistic clues on sexually dimorphic differences seen in interorgan communication, metabolic disease, neurological disorders, and more.

There has been rapid growth in the use of Drosophila and other invertebrate systems to dissect mechanisms governing metabolism. New assays and approaches to physiology have aligned with superlative genetic tools in fruit flies to provide a powerful platform for posing new questions, or dissecting classical problems in metabolism and disease genetics. In multiple examples, these discoveries exploit experimental advantages as yet unavailable in mammalian systems. Here we illustrate how fly studies have addressed long-standing questions in three broad areas – inter-organ signalling through hormonal or neural mechanisms governing metabolism, intestinal interoception and feeding, and the cellular and signalling basis of sexually dimorphic metabolism and physiology – and how these findings relate to human (patho)physiology. The imaginative application of integrative physiology and related approaches in flies to questions in metabolism is expanding, and will be an engine of discovery, revealing paradigmatic features of metabolism underlying human diseases, and physiological equipoise in health.

Reproduction induces increased food intake across females of many animal species1–4, providing a physiologically relevant paradigm for the exploration of appetite regulation. Here, by examining the diversity of enteric neurons in Drosophila melanogaster, we identify a key role for gut-innervating neurons with sex- and reproductive state-specific activity in sustaining the increased food intake of mothers during reproduction. Steroid and enteroendocrine hormones functionally remodel these neurons, which leads to the release of their neuropeptide onto the muscles of the crop—a stomach-like organ—after mating. Neuropeptide release changes the dynamics of crop enlargement, resulting in increased food intake, and preventing the post-mating remodelling of enteric neurons reduces both reproductive hyperphagia and reproductive fitness. The plasticity of enteric neurons is therefore key to reproductive success. Our findings provide a mechanism to attain the positive energy balance that sustains gestation, dysregulation of which could contribute to infertility or weight gain. A multi-organ circuit is activated in female flies after mating, leading to changes in enteric neurons that increase food intake.

The small intestine displays marked anatomical and functional plasticity that includes adaptive alterations in adult gut morphology, enteroendocrine cell profile and their hormone secretion, as well as nutrient utilization and storage. In this Perspective, we examine how shifts in dietary and environmental conditions bring about changes in gut size, and describe how the intestine adapts to changes in internal state, bowel resection and gastric bypass surgery. We highlight the critical importance of these intestinal remodelling processes in maintaining energy balance of the organism, and in protecting the metabolism of other organs. The intestinal resizing is supported by changes in the microbiota composition, and by activation of carbohydrate and fatty acid metabolism, which govern the intestinal stem cell proliferation, intestinal cell fate, as well as survivability of differentiated epithelial cells. The discovery that intestinal remodelling is part of the normal physiological adaptation to various triggers, and the potential for harnessing the reversible gut plasticity, in our view, holds extraordinary promise for developing therapeutic approaches against metabolic and inflammatory diseases.

Individual hosts within populations often show inter-individual variation in their susceptibility to bacterial pathogen-related disease. Utilizing Drosophila, we highlight that phenotypic variation in host-pathogen susceptibility within populations is driven by energetic trade-offs, facilitated by infection-mediated changes in glutamate metabolism. Furthermore, host-pathogen susceptibility is conditioned by life-history, which adjusts immune-metabolic sensing in muscle to direct vitamin-dependent re-allocation of host energy substrates from adipose (muscle-adipose axis). Life-history conditions inter-individual variation in the activation strength of intra-muscular NF-kB/innate immune signaling. Limited intra-muscular NF-kB/innate immune signaling activity allows for infection-mediated increases in mitochondrial biogenesis and function, which stimulates glutamate dehydrogenase (Gdh)-dependent synthesis of glutamate. Muscle-derived glutamate acts as systemic metabolite to promote lipid mobilization through modulating vitamin B enzymatic cofactor transport and function in adipose. This energy substrate re-allocation improves pathogen clearance and boosts host survival. Finally, life-history events that adjust energetic trade-offs can shape inter-individual variation in host-pathogen susceptibility after infection.

Summary Animals display selective escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximizing chances of survival, yet the underlying network mechanisms are so far not fully understood. Using synapse-level reconstruction of the Drosophila larval network paired with physiological and behavioral readouts, we uncovered a circuit that gates selective escape behavior for noxious light through acute and input-specific neuropeptide action. Sensory neurons required for avoidance of noxious light and escape in response to harsh touch, each converge on discrete domains of neuromodulatory hub neurons. We show that acute release of hub neuron-derived insulin-like peptide 7 (Ilp7) and cognate relaxin family receptor (Lgr4) signaling in downstream neurons are required for noxious light avoidance, but not harsh touch responses. Our work highlights a role for compartmentalized circuit organization and neuropeptide release from regulatory hubs, acting as central circuit elements gating escape responses.

In our 20th anniversary year, we reflect on how fields have changed since our first issue and here look to the future. In this collection of Voices, our writers speculate on the future: in terms of philosophy, cell states, cell processes, and then how to model cell systems.

There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell-type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post-translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, “Metabolic Decisions in Development and Disease.” The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer-mediated changes in metabolism.

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work inDrosophilashowed that body size plasticity was higher in females, yet the mechanisms underlying increased female body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-biased increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This sex-biased upregulation of IIS activity was triggered by a diet-induced increase instuntedmRNA in females, and requiredDrosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination genetransformerpromotes the diet-induced increase instuntedmRNA via transcriptional coactivator Spargel to regulate the male-female difference in body size plasticity. Together, these findings provide vital insight into conserved mechanisms underlying the sex difference in nutrient-dependent body size plasticity.

Animals display a plethora of escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximize chances of survival. We uncovered a somatosensory network in Drosophila larvae that encodes two escape behaviors through input-specific neuropeptide action. Sensory neurons required for avoidance of noxious light and escape in response to harsh touch, each converge on discrete domains of the same neuromodulatory hub neurons. These gate harsh touch responses via short Neuropeptide F, but noxious light avoidance via compartmentalized, acute Insulin-like peptide 7 action and cognate Relaxin-family receptor signaling in connected downstream neurons. Peptidergic hub neurons can thus act as central circuit elements for first order processing of converging sensory inputs to gate specific escape responses.One Sentence SummaryCompartment-specific neuropeptide action regulates sensory information processing to elicit discrete escape behavior in Drosophila larvae.

[Graphic][1] Irene Miguel-Aliaga is Professor of Genetics and Physiology at Imperial College London, and Section Chair and Programme Leader at the Medical Research Council London Institute of Medical Sciences (LMS). Her laboratory is interested in metabolism, organ plasticity and ‘

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment. However, the sample preparations for such imaging are often onerous, and their capability for antigen detection is limited. Here, we describe FLASH (fast light-microscopic analysis of antibody-stained whole organs), a simple, rapid, fully customizable technique for molecular phenotyping of intact tissue volumes. FLASH utilizes non-degradative epitope recovery and membrane solubilization to enable the detection of a multitude of membranous, cytoplasmic and nuclear antigens in whole mouse organs and embryos, human biopsies, organoids and Drosophila. Retrieval and immunolabeling of epithelial markers, an obstacle for previous clearing techniques, can be achieved with FLASH. Upon volumetric imaging, FLASH-processed samples preserve their architecture and integrity and can be paraffin-embedded for subsequent histopathological analysis. The technique can be performed by scientists trained in light microscopy and yields results in1 week.

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work inDrosophilashowed that body size plasticity was higher in females, yet the mechanisms underlying the sex difference in body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-specific increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This increased IIS activity was triggered by a diet-induced increase instunted, and requiredDrosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination genetransformerregulates the diet-induced increase instuntedand IIS activity, and mediates the sex difference in body size plasticity. This identifies one sex-specific mechanism underlying the nutrient-dependent regulation of IIS activity and body size plasticity, providing vital insight into conserved mechanisms that mediate sex differences in phenotypic plasticity.

In cells, organs and whole organisms, nutrient sensing is key to maintaining homeostasis and adapting to a fluctuating environment1. In many animals, nutrient sensors are found within the enteroendocrine cells of the digestive system; however, less is known about nutrient sensing in their cellular siblings, the absorptive enterocytes1. Here we use a genetic screen in Drosophila melanogaster to identify Hodor, an ionotropic receptor in enterocytes that sustains larval development, particularly in nutrient-scarce conditions. Experiments in Xenopus oocytes and flies indicate that Hodor is a pH-sensitive, zinc-gated chloride channel that mediates a previously unrecognized dietary preference for zinc. Hodor controls systemic growth from a subset of enterocytes—interstitial cells—by promoting food intake and insulin/IGF signalling. Although Hodor sustains gut luminal acidity and restrains microbial loads, its effect on systemic growth results from the modulation of Tor signalling and lysosomal homeostasis within interstitial cells. Hodor-like genes are insect-specific, and may represent targets for the control of disease vectors. Indeed, CRISPR–Cas9 genome editing revealed that the single hodor orthologue in Anopheles gambiae is an essential gene. Our findings highlight the need to consider the instructive contributions of metals—and, more generally, micronutrients—to energy homeostasis.

Graphical abstract, Highlights • The gastrointestinal tract is innervated by the ENS and connected with the CNS. • The gut-brain axis adjusts gut physiology in response to environmental cues and internal state. • The anatomy and functions of gastrointestinal neurons can change during an organism’s lifetime. • This plasticity is modulated by factors such as microbiota, nutrients, sex and age., The gastrointestinal tract is innervated by its own enteric nervous system and by extrinsic neurons that connect it with the central nervous system. Innervation allows the gastrointestinal tract to sense and respond to diverse stimuli, adjusting motility and secretion, but also affecting our physiology, behaviour and immunity. The mechanisms underlying the formation of gastrointestinal neurons are beginning to be elucidated; those that keep them plastic over an organism’s lifetime remain to be explored. Here, we review the effects of microbiota, nutrients, sex and ageing on the morphology and function of gastrointestinal innervation in mammals, and discuss how this plasticity shapes gut-brain crosstalk and whole-body physiology. We also highlight insights gained by nascent studies of the enteric innervation of Drosophila melanogaster.

Summary Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized., Graphical Abstract, Highlights • Intestinal carbohydrate metabolism is male-biased and region-specific • Testes masculinize gut sugar handling by promoting enterocyte JAK-STAT signaling • The male intestine secretes citrate to the adjacent testes • Gut-derived citrate promotes food intake and sperm maturation, Inter-organ communication couples diet with gamete production. The male gonad promotes sex differences in carbohydrate metabolism within an adjacent intestinal portion via JAK-STAT signalling. In response to this gonadal signal, gut-derived citrate controls food intake and sperm maturation.

The gastrointestinal tract has recently come to the forefront of multiple research fields. It is now recognized as a major source of signals modulating food intake, insulin secretion and energy balance. It is also a key player in immunity and, through its interaction with microbiota, can shape our physiology and behavior in complex and sometimes unexpected ways. The insect intestine had remained, by comparison, relatively unexplored until the identification of adult somatic stem cells in the Drosophila intestine over a decade ago. Since then, a growing scientific community has exploited the genetic amenability of this insect organ in powerful and creative ways. By doing so, we have shed light on a broad range of biological questions revolving around stem cells and their niches, interorgan signaling and immunity. Despite their relatively recent discovery, some of the mechanisms active in the intestine of flies have already been shown to be more widely applicable to other gastrointestinal systems, and may therefore become relevant in the context of human pathologies such as gastrointestinal cancers, aging, or obesity. This review summarizes our current knowledge of both the formation and function of the Drosophila melanogaster digestive tract, with a major focus on its main digestive/absorptive portion: the strikingly adaptable adult midgut.

Summary During adaptive angiogenesis, a key process in the etiology and treatment of cancer and obesity, the vasculature changes to meet the metabolic needs of its target tissues. Although the cues governing vascular remodeling are not fully understood, target-derived signals are generally believed to underlie this process. Here, we identify an alternative mechanism by characterizing the previously unrecognized nutrient-dependent plasticity of the Drosophila tracheal system: a network of oxygen-delivering tubules developmentally akin to mammalian blood vessels. We find that this plasticity, particularly prominent in the intestine, drives—rather than responds to—metabolic change. Mechanistically, it is regulated by distinct populations of nutrient- and oxygen-responsive neurons that, through delivery of both local and systemic insulin- and VIP-like neuropeptides, sculpt the growth of specific tracheal subsets. Thus, we describe a novel mechanism by which nutritional cues modulate neuronal activity to give rise to organ-specific, long-lasting changes in vascular architecture., Graphical Abstract, Highlights • The Drosophila tracheal system exhibits nutrient-dependent plasticity • Tracheal plasticity is organ specific and metabolically significant • Nutrient- and hypoxia-responsive neurons drive adaptive tracheation • Distinct insulin-like and Pdf neuropeptides control organ-specific tracheal branching, Previously unrecognized nutrient-dependent plasticity of the Drosophila tracheal system drives metabolic change and is regulated by distinct populations of nutrient- and oxygen-responsive neurons.

View Large Image | View Hi-Res Image | Download PowerPoint SlideIrene Miguel-Aliaga is Professor of Genetics and Physiology at Imperial College London and Programme Leader at the London MRC London Institute of Medical Sciences. Following completion of a PhD with Kay Davies at the University of Oxford, she explored how neurons acquire their identity during postdoctoral work, first with Stefan Thor at Harvard and Linkoping University and then with Alex Gould at NIMR (now Crick Institute), London. Irene has an interest in cellular and organ plasticity. First at Cambridge and now in London, her research group is exploring the mechanisms by which organs sense and respond to change: the molecules, cellular events and physiological adaptations involved. Their work has primarily focused on the fly intestine and its neurons, which they have used to discover that digestive systems know their sex, are resized and reprogrammed during reproduction, and use their neurons to orchestrate metabolic adaptations to malnutrition and reproduction. Irene was elected to the EMBO YIP programme in 2012 and is the recipient of an ERC Starting Grant. You can follow what her lab is up to on Twitter @FlyGutLab.What turned you on to biology in the first place? As a little girl I was not fond of princesses. I preferred to star gaze, walk on wet grass, watch raindrops and draw different kinds of bugs — it all felt so exotic from the flat in urban Barcelona where I grew up. That girl turned into an easily bored bookworm who, having read Carl Sagan’s Cosmos, Gerald Durrell’s My Family and other Animals and Jane Goodall’s accounts of what it’s like to live with chimpanzees in Africa, wondered whether she might be able to turn her independence and scientific mind into some sort of adventure. As a teenager, I got a bit distracted by a saxophone and the discovery of other humans, so I guess it was Boris Vian and his two wonderful books L’Arrache-coeur and, particularly, L’Herbe Rouge, that revived my passion for science. He seamlessly combined science with humour, music, romanticism, politics and a taste for absurdity, making it part of an everyday adventure that suddenly seemed a lot less remote from my own existence.I loved learning about biology, first at university but also well into my postdoc. But it was a time also plagued with self-doubt. Would I be smart enough? Would I have what it takes, whatever that might be? It took me a long time to realise that I was trying too hard to conform and be like everyone else, when I should have been nurturing what was different. Gaining that self-awareness and developing more confidence not only felt liberating, but it greatly improved my science thereafter.What do you like most about your job? It indulges my incurable and persistent curiosity. I am also a very visual person; I seem to derive joy from anything that looks beautiful or striking, and this includes the scientific images we generate. But I guess my main drive is that I just love questions — unexpected, logically structured questions. If they’re really good questions, I don’t even mind if they are not answered! I feel privileged to make a living out of asking them, and I am particularly pleased when, through the efforts of everyone in the lab, we manage to find unexpected answers to some of them. So I like surprises too… like most of us.My science also seems to have turned out to be rather personal and visceral in more ways than one — perhaps this is why we work with guts. I first realised this soon after the birth of my two children as I was writing a paper about how physiology changes during reproduction. I think it was Polanyi who said that there is no science without passion and, in my case, my scientific output has been, at times, reflective of my personal passions and obsessions.So what scientific questions excite you? In the lab, I find plasticity fascinating — are some cells or cellular states more plastic than others at every level? If so, why? Our recent work suggests that the plasticity of gut cells is sexually dimorphic. Female cells are more plastic — does that make them less stable, robust, resourceful or prone to crash? When cellular plasticity is considered at the organ level, these questions acquire behavioural and physiological implications; in the context of sex differences, is the sole purpose of this enhanced plasticity in females to allow the organ/organism to cope with reproduction?But I am generally interested in all sorts of things. As a community, we are working on so few of them — often with several people tackling the same question in exactly the same way. And we are often unable to answer the simple yet fascinating questions that a curious child may ask. If you buy me a beer, I will go on about how we may have become excessively fixated with genes and epigenetics, and I am always curious about alternative mechanisms of information transfer. I also find it intriguing that single cells can display agency and behaviours that we often attribute to complex intercellular processes in multicellular organisms (e.g. perseverance, decision making). What is that saying about how we study these processes? As seasons go by, I am also fascinated by how much they do to our biology and how little we know about it.Do you have any scientific heroes? I do have my own favourite scientific minds, conflicted and unorthodox, with whom I enjoy talking over drinks or dinner. But I try not to have scientific heroes — they often fail to live up to the hype and we already have too much of a celebrity culture in biology. I have spent too many dinners discussing Dr. X and Prof. Y. It is hard not to do it because we all like stories full of heroes and villains, and grey areas can be boring. But a good storyteller should be able to tell an enticing and memorable story of an amazing finding and the long, arduous path to its discovery — which may include many people we have not even heard of.Any advice for someone starting a career in science? There may not be one-size-fits-all advice — some people listen to others too much, some should listen more. But perhaps we should all try to have fun. The older generation managed it very well, but younger scientists seem to find it harder because of various pressures — short-term funding etc. Finding joy in what you do may require pursuing your interests and passions, even if they are unusual. In my case, this involved cataloguing different kinds of fly excreta, which at the time was met with a mixture of amusement at best and scepticism and disgust at worst. But I have faith in fun; that work led to many of the projects and findings that have kept us motivated, productive and funded in recent years. It also left me with an excellent collection of poo memorabilia, which may be my most significant contribution to the next generation.Do you feel a push towards more applied science? Should we still use model systems? We need to acknowledge the difference between ‘applied’ and ‘human’. There seems to be a push towards using human material in research (e.g. embryonic stem cells, organoids, patient tissue) with the underlying assumption that we can only prevent or treat human disease by studying human disease. But we can also improve human health by understanding human health, as well as the bacteria that infect us, the pests that eat our crops, the mosquitoes that bite us and the parasites that are costly to livestock producers. With this broader picture in mind, should we still use model systems? Absolutely. I have always wondered what ‘model’ means anyway — model for what? It sounds too hypothesis-driven. It seems to me that an effective path to translation is to use whatever organism/system is likely to lead to new findings (Drosophila is a powerful example) and then explore any potential applications of such findings. The latter process may require a bit of lateral, outside-the-box thinking; the CRISPR story provides an obvious example. Another example closer to my PhD work is the work on alternative splicing — a fundamental cellular process — that led to the development of nusinersen: a promising drug for the treatment of spinal muscular atrophy. Nurturing and funding such creativity and lateral thinking is key to effective translation.How else can we do better science? I often see the lab as a building site that needs builders, bulldozers and surveyors. Relentless data generation can send you down the wrong scientific path, too much revolutionising/dogma-breaking and nothing meaningful will get built, and continuously checking the foundations may stall progress. So a scientific team needs builders, bulldozers and surveyors in the right ratio. Because they’re not following an architect’s plan, the team will also need time to fail, prove themselves wrong, wonder how and why, and start again. The current system is not particularly conducive to this process and could benefit from longer-term funding, publishing less and providing vehicles (journals, talk formats) to present, report and discuss negative results.How about the work–life balance? Another phrase we could do without… It makes it sound like work is bad and life is good, and that they must be distinct. Just as I bring science to my life — for example by mixing cream of tartar, baking soda and food dyes to make bath bombs with my little girls — we should bring more life to the workplace by making it more ‘friends and family’ friendly. Research institutes should have nurseries, bars, green open spaces and somewhere to nap. Sleep–life balance: that is a better concept… I could also go on for hours about how we underestimate the importance of sleep!If you hadn’t made it as a scientist, what would you have become? A failed novelist, a lousy saxophone player AND a tormented wanabee astronaut. Or a time traveller. So it’s just as well that I have made it.

The digestive tract plays a central role in the digestion and absorption of nutrients. Far from being a passive tube, it provides the first line of defense against pathogens and maintains energy homeostasis by exchanging neuronal and endocrine signals with other organs. Historically neglected, the gut of the fruit fly Drosophila melanogaster has recently come to the forefront of Drosophila research. Areas as diverse as stem cell biology, neurobiology, metabolism, and immunity are benefitting from the ability to study the genetics of development, growth regulation, and physiology in the same organ. In this review, we summarize our knowledge of the Drosophila digestive tract, with an emphasis on the adult midgut and its functional underpinnings.

During the development of locomotion circuits it is essential that motoneurons with distinct subtype identities select the correct trajectories and target muscles. In vertebrates, the generation of motoneurons and myelinating glia depends on Olig2, one of the five Olig family bHLH transcription factors. We investigated the so far unknown function of the single Drosophila homolog Oli. Combining behavioral and genetic approaches, we demonstrate that oli is not required for gliogenesis, but plays pivotal roles in regulating larval and adult locomotion, and axon pathfinding and targeting of embryonic motoneurons. In the embryonic nervous system, Oli is primarily expressed in postmitotic progeny, and in particular, in distinct ventral motoneuron subtypes. oli mediates axonal trajectory selection of these motoneurons within the ventral nerve cord and targeting to specific muscles. Genetic interaction assays suggest that oli acts as part of a conserved transcription factor ensemble including Lim3, Islet and Hb9. Moreover, oli is expressed in postembryonic leg-innervating motoneuron lineages and required in glutamatergic neurons for walking. Finally, over-expression of vertebrate Olig2 partially rescues the walking defects of oli-deficient flies. Thus, our findings reveal a remarkably conserved role of Drosophila Oli and vertebrate family members in regulating motoneuron development, while the steps that require their function differ in detail., Highlights ► Drosophila Oli is expressed in embryonic ventral motoneuron subtypes. ► oli controls axonal trajectory selection and muscle targeting during embryogenesis. ► Oli acts as part of a conserved transcription factor ensemble that includes Hb9. ► Oli is expressed in postembryonic leg-innervating motoneuron lineages. ► Oli is required in glutamatergic neurons for adult locomotion.

Irene Miguel-Aliaga left sunny Barcelona to pursue a PhD at Oxford University in the laboratory of Kay Davies. She did her postdoctorate at Harvard University in Stefan Thor's lab, and briefly relocated with him to Sweden before coming back to the UK. She continued her postdoctoral work and developed her current research interests as a Marie Curie Fellow in the lab of Alex Gould at the National Institute for Medical Research in London. She established her own lab at the University of Cambridge in 2008, thanks to a Wellcome Trust Career Development Fellowship. In 2012 she moved to London and is currently a Programme Leader at the Medical Research Council Clinical Sciences Centre and a Reader at Imperial College London. Irene was elected to the EMBO Young Investigator programme and holds an ERC Starting Grant. Her lab investigates how gut cells maintain homeostasis and communicate with cells of other tissues and organs.

Sex differences in physiology and disease susceptibility are commonly attributed to developmental and/or hormonal factors, but there is increasing realization that cell-intrinsic mechanisms play important and persistent roles. Here we use the Drosophila melanogaster intestine to investigate the nature and importance of cellular sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncovers the key role this identity has in controlling organ size, reproductive plasticity and response to genetically induced tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms that control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognized.

Autosomal recessive spinal muscular atrophy (SMA) is linked to mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated at several levels of mRNA biogenesis and is expressed ubiquitously. Studies in various model organisms have shown that the loss of function of the SMN gene leads to embryonic lethality. The human contains two genes encoding for SMN protein and in patients one of these is disrupted. It is thought the remaining low levels of protein produced by the second SMN gene do not suffice and result in the observed specific loss of lower motor neurons and muscle wasting. The early lethality in the animal mutants has made it difficult to understand why primarily these tissues are affected. We have isolated a Drosophila smn mutant. The fly alleles contain point mutations in smn similar to those found in SMA patients. We find that zygotic smn mutant animals show abnormal motor behavior and that smn gene activity is required in both neurons and muscle to alleviate this phenotype. Physiological experiments on the fly smn mutants show that excitatory post-synaptic currents are reduced while synaptic motor neuron boutons are disorganized, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction is severely reduced. This new Drosophila model for SMA thus proposes a functional role for SMN at the neuromuscular junction in the generation of neuromuscular defects.

Individual neurons express only one or a few of the many identified neurotransmitters and neuropeptides, but the molecular mechanisms controlling their selection are poorly understood. In the Drosophila ventral nerve cord, the six Tv neurons express the neuropeptide gene FMRFamide. Each Tv neuron resides within a neuronal cell group specified by the LIM-homeodomain gene apterous. We find that the zinc-finger gene squeeze acts in Tv cells to promote their unique axon pathfinding to a peripheral target. There, the BMP ligand Glass bottom boat activates the Wishful thinking receptor, initiating a retrograde BMP signal in the Tv neuron. This signal acts together with apterous and squeeze to activate FMRFamide expression. Reconstituting this “code,” by combined BMP activation and apterous/squeeze misexpression, triggers ectopic FMRFamide expression in peptidergic neurons. Thus, an intrinsic transcription factor code integrates with an extrinsic retrograde signal to select a specific neuropeptide identity within peptidergic cells.

Around 100 researchers gathered at the eighteenth EMBO Conference on ‘The Molecular and Developmental Biology of Drosophila', which took place in Crete in June 2012. Whether deconstructing or integrating at the genetic, cellular or organ level, the talks highlighted the synergy of combining methods, approaches and disciplines in this increasingly versatile model system.

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., This work was funded by grants from the Wellcome Trust, European Research Council and the Medical Research Council (WT083559, ERCStG 310411 and intramural to IM-A), Generalitat Valenciana (PROMETEO II/2013/001 to MD), Spanish Ministry of Science (BFU2009-09074, SAF2012-35181, CSD2007-00023 to MD), Botin Foundation (to MD), and the Singapore National Research Foundation (RF2010-06 to JYY). TR held a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft and IM-A is a member of, and is supported by, the EMBO Young Investigator Programme.

We have characterized the developmental expression pattern of the Caenorhabditis elegans homologue of the mouse ky gene. The Ky protein has a putative key function in muscle development and has homologues in invertebrates, fungi and a cyanobacterium. The C. elegans Ky homologue gene has been named ltd-1 for LIM and transglutaminase domains gene. The LTD-1::GFP construct is expressed in developing hypodermal cells from the twofold stage embryo through adulthood. These data define the ltd-1 gene as a novel marker for C. elegans epithelial cell development.

Mutations in the gene encoding the Survival Motor Neuron (SMN) protein are responsible for autosomal recessive proximal spinal muscular atrophy (SMA). SMN orthologues have been identified in the nematode worm Caenorhabditis elegans and the yeast Schizosaccharomyces pombe but, to date, no human paralogues have been described. Here we describe identification and characterization of an SMN-related protein (SMNrp) gene that encodes a novel protein of 239 amino acids, which has recently been identified as a constituent of the spliceosome complex and designated SPF30. Significant similarity to the SMN protein is apparent only within a central region of SMNrp that represents a tudor domain. The SMNrp/SPF30 gene has been mapped to chromosome 10q23. It is differentially expressed, with abundant levels in skeletal muscle. An exclusively nuclear localization for SMNrp in cultured cells and muscle sections was revealed using GFP fusion constructs and thereafter confirmed with a polyclonal antibody raised against SMNrp. Overexpression of SMNrp as a fusion protein in HeLa cells in culture induced dose-dependent apoptosis with positive TUNEL staining. In addition to a possible role for this protein as a pro-apoptotic factor, SMN and its related protein share significant similarities in sequence and cellular function.