57 results found
Miguel-Aliaga I, 2022, Let's talk about (biological) sex, Nature Reviews Molecular Cell Biology, Vol: 23, Pages: 227-228, ISSN: 1471-0072
Imambocus BN, Zhou F, Formozov A, et al., 2022, A neuropeptidergic circuit gates selective escape behavior of Drosophila larvae, Current Biology, Vol: 32, Pages: 149-163.e8, ISSN: 0960-9822
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.
Mineo A, Miguel-Aliaga I, 2021, Defend or reproduce? Muscle-derived glutamate determines an immune/reproductive energetic tradeoff, Cell Metabolism, Vol: 33, Pages: 2307-2309, ISSN: 1550-4131
There are dramatic disparities in infection susceptibility within populations. In this issue of Cell Metabolism, Zhao and Karpac uncover a muscle-adipose-gut axis in Drosophila that explains variability in pathogen susceptibility. The degree of intramuscular NF-kB activation accounts for differences in circulating glutamate, which enhances resistance at the expense of reproduction.
Cable J, Pourquie O, Wellen KE, et al., 2021, Metabolic decisions in development and disease-a Keystone Symposia report, Annals of the New York Academy of Sciences, Vol: 1506, Pages: 55-73, ISSN: 0077-8923
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.
Kim SK, Tsao DD, Suh GSB, et al., 2021, Discovering signaling mechanisms governing metabolism and metabolic diseases with Drosophila, Cell Metabolism, Vol: 33, Pages: 1279-1292, ISSN: 1550-4131
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 signaling through hormonal or neural mechanisms governing metabolism, intestinal interoception and feeding, and the cellular and signaling 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.
Millington JW, Brownrigg GP, Chao C, et al., 2021, Female-blase upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity, eLife, Vol: 10, Pages: 1-36, ISSN: 2050-084X
Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed 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 in stunted mRNA in females, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination gene transformer promotes the diet-induced increase in stunted mRNA 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.
Messal HA, Almagro J, Zaw Thin M, et al., 2021, Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH, Nature Protocols, Vol: 16, Pages: 239-262, ISSN: 1750-2799
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 in <1 week.
Miguel-Aliaga I, Hadjieconomou D, King G, et al., 2020, Enteric neurons increase maternal food intake during reproduction, Nature, Vol: 587, Pages: 455-459, ISSN: 0028-0836
Reproduction induces increased food intake across females of many animal species1,2,3,4, 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.
Brown K, 2020, An interview with Irene Miguel-Aliaga, DEVELOPMENT, Vol: 147, ISSN: 0950-1991
Ameku T, Beckwith H, Blackie L, et al., 2020, Food, microbes, sex and old age: on the plasticity of gastrointestinal innervation, Current Opinion in Neurobiology, Vol: 62, Pages: 83-91, ISSN: 0959-4388
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.
Redhai S, Pilgrim C, Gaspar P, et al., 2020, An intestinal zinc sensor regulates food intake and developmental growth, Nature, Vol: 580, Pages: 263-268, ISSN: 0028-0836
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.
Milona A, Massafra V, Vos H, et al., 2019, Steroidogenic control of liver metabolism through a nuclear receptor-network, Molecular Metabolism, Vol: 30, Pages: 221-229, ISSN: 2212-8778
OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown. METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1. CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.
Hudry B, de Goeij E, Mineo A, et al., 2019, Sex differences in intestinal carbohydrate metabolism promote food intake and sperm maturation, Cell, Vol: 178, Pages: 901-918.e16, ISSN: 0092-8674
Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remainincompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate howgut-derived signals contribute to sex differences in whole-body physiology. We find thatcarbohydrate handling is male-biased in a specific portion of the intestine. In contrast to knownsexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism areextrinsically controlled by the adjacent male gonad, which activates JAK-STAT signalling inenterocytes within this intestinal portion. Sex reversal experiments establish roles for this malebiased intestinal metabolic state in controlling food intake and sperm production through gutderived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, andreveals that metabolic communication across organs is physiologically significant. The instructiverole of citrate in inter-organ communication may be significant in more biological contexts thanpreviously recognised.
Miguel-Aliaga I, Jasper H, Lemaitre B, 2018, Anatomy and physiology of the digestive tract of drosophila melanogaster, Genetics, Vol: 210, Pages: 357-396, ISSN: 0016-6731
The gastrointestinal tract has recently come to the forefront of multiple research fields. It is now recognized as a major sourceof signals modulating food intake, insulin secretion and energy balance. It is also a key player in immunity and, through its interaction withmicrobiota, can shape our physiology and behavior in complex and sometimes unexpected ways. The insect intestine had remained, bycomparison, relatively unexplored until the identification of adult somatic stem cells in the Drosophila intestine over a decade ago. Sincethen, a growing scientific community has exploited the genetic amenability of this insect organ in powerful and creative ways. By doingso, we have shed light on a broad range of biological questions revolving around stem cells and their niches, interorgan signaling andimmunity. Despite their relatively recent discovery, some of the mechanisms active in the intestine of flies have already been shown to bemore widely applicable to other gastrointestinal systems, and may therefore become relevant in the context of human pathologies such asgastrointestinal cancers, aging, or obesity. This review summarizes our current knowledge of both the formation and function of theDrosophila melanogaster digestive tract, with a major focus on its main digestive/absorptive portion: the strikingly adaptable adult midgut.
Grmai L, Hudry B, Miguel-Aliaga I, et al., 2018, Chinmo prevents transformer alternative splicing to maintain male sex identity, PLoS Genetics, Vol: 14, Pages: 1-27, ISSN: 1553-7390
Reproduction in sexually dimorphic animals relies on successful gamete production, executed by the germline and aided by somatic support cells. Somatic sex identity in Drosophila is instructed by sex-specific isoforms of the DMRT1 ortholog Doublesex (Dsx). Female-specific expression of Sex-lethal (Sxl) causes alternative splicing of transformer (tra) to the female isoform traF. In turn, TraF alternatively splices dsx to the female isoform dsxF. Loss of the transcriptional repressor Chinmo in male somatic stem cells (CySCs) of the testis causes them to “feminize”, resembling female somatic stem cells in the ovary. This somatic sex transformation causes a collapse of germline differentiation and male infertility. We demonstrate this feminization occurs by transcriptional and post-transcriptional regulation of traF. We find that chinmo-deficient CySCs upregulate tra mRNA as well as transcripts encoding tra-splice factors Virilizer (Vir) and Female lethal (2)d (Fl(2)d). traF splicing in chinmo-deficient CySCs leads to the production of DsxF at the expense of the male isoform DsxM, and both TraF and DsxF are required for CySC sex transformation. Surprisingly, CySC feminization upon loss of chinmo does not require Sxl but does require Vir and Fl(2)d. Consistent with this, we show that both Vir and Fl(2)d are required for tra alternative splicing in the female somatic gonad. Our work reveals the need for transcriptional regulation of tra in adult male stem cells and highlights a previously unobserved Sxl-independent mechanism of traF production in vivo. In sum, transcriptional control of the sex determination hierarchy by Chinmo is critical for sex maintenance in sexually dimorphic tissues and is vital in the preservation of fertility.
Perea D, Guiu J, Hudry B, et al., 2017, Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia., EMBO Journal, Vol: 36, Pages: 3029-3045, ISSN: 0261-4189
Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homoeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease.
Miguel-Aliaga I, 2017, Sex, reproduction and intestinal plasticity, 18th International Congress of Developmental Biology, Publisher: Elsevier, Pages: S5-S5, ISSN: 0925-4773
Miguel-Aliaga I, 2017, Irene Miguel-Aliaga, Current Biology, Vol: 27, Pages: R286-R287, ISSN: 1879-0445
Hudry B, Khadayate S, Miguel-Aliaga I, 2016, The sexual identity of adult intestinal stem cells controls organ size and plasticity, Nature, Vol: 530, Pages: 344-348, ISSN: 1476-4687
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.
Miguel-Aliaga I, 2015, Cell scientist to watch - Irene Miguel-Aliaga, Journal of Cell Science, Vol: 128, Pages: 3519-3520, ISSN: 1477-9137
Reiff T, Jacobson J, Cognigni P, et al., 2015, Endocrine remodelling of the adult intestine sustains reproduction in Drosophila., eLife, Vol: 4, ISSN: 2050-084X
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.
Soba P, Han C, Zheng Y, et al., 2015, The Ret receptor regulates sensory neuron dendrite growth and integrin mediated adhesion, eLife, Vol: 4, ISSN: 2050-084X
Wayland MT, Defaye A, Rocha J, et al., 2014, Spotting the differences: Probing host/microbiota interactions with a dedicated software tool for the analysis of faecal outputs in Drosophila, JOURNAL OF INSECT PHYSIOLOGY, Vol: 69, Pages: 126-135, ISSN: 0022-1910
Martorell O, Merlos-Suarez A, Campbell K, et al., 2014, Conserved Mechanisms of Tumorigenesis in the Drosophila Adult Midgut, PLOS One, Vol: 9, ISSN: 1932-6203
Whereas the series of genetic events leading to colorectal cancer (CRC) have been well established, the precise functionsthat these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized.Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducingbenign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Rasmutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila’s intestinesshare many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activationof the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show thatcompound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-likeoutgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of celldifferentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markerspresent in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration inintestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeuticcompounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila,providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation andprogression.
Linneweber GA, Jacobson J, Busch KE, et al., 2014, Neuronal control of metabolism through nutrient-dependent modulation of tracheal branching, Cell, Vol: 156, Pages: 69-83, ISSN: 0092-8674
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.
Sarraf-Zadeh L, Christen S, Sauer U, et al., 2013, Local requirement of the Drosophila insulin binding protein imp-L2 in coordinating developmental progression with nutritional conditions, DEVELOPMENTAL BIOLOGY, Vol: 381, Pages: 97-106, ISSN: 0012-1606
Lemaitre B, Miguel-Aliaga I, 2013, The Digestive Tract of Drosophila melanogaster, ANNUAL REVIEW OF GENETICS, VOL 47, Vol: 47, Pages: 377-404, ISSN: 0066-4197
Miguel-Aliaga I, Oliver B, Teleman AA, 2012, The flies of Icarus: science with wings in Crete, EMBO REPORTS, Vol: 13, Pages: 945-947, ISSN: 1469-221X
Oyallon J, Apitz H, Miguel-Aliaga I, et al., 2012, Regulation of locomotion and motoneuron trajectory selection and targeting by the Drosophila homolog of Olig family transcription factors, DEVELOPMENTAL BIOLOGY, Vol: 369, Pages: 261-276, ISSN: 0012-1606
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