Biology subjects

Miguel-Aliaga, I.

Publications and source records attributed to Miguel-Aliaga, I..

7 recordsLinked to original sources

bioRxiv2026

Genetic sex of enteric neurons enables ovarian relaxin togate maternal gut plasticity

Animals must align intestinal plasticity and feeding with reproductive state, yet the checkpoint that gates these adaptations is unknown. Here we show that an ovary-to-enteric-neuron axis gates the onset of maternal gut plasticity in Drosophila. Genetic sex establishes endocrine competence in a subset of enteric neurons via the sex determination pathway, enabling female-specific expression of the relaxin-family receptor Lgr3. After mating, steroid signalling increases Lgr3 receptor expression, priming these neurons for reproductive adaptation. Once oocytes mature fully, follicle cells secrete the relaxin-like hormone dILP8, which activates Lgr3 to trigger gut enlargement and increased feeding. Disrupting the sex determination pathway in enteric neurons, Lgr3, or ovarian dILP8 prevents gut enlargement and reduces feeding. Thus, genetic sex establishes competence, steroid signalling primes it, and ovarian relaxin triggers it, defining a maternal intestinal plasticity checkpoint that ensures gut adaptations initiate only once reproduction is underway and energy demands peak. Our findings delineate an ovary-to-enteric-neuron axis that couples reproductive state to maternal gut plasticity.

physiology↗

bioRxiv2025

Mesodermal-specific MECP2 expression in Drosophila induces visceral and skeletal muscle defects rescued by butyrate supplementation

BackgroundPatients affected by Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) experience disabling muscle weakness and gastrointestinal dysmotility of unclear origin. Whether these defects arise cell-autonomously, rather than secondarily to neural dysfunction, and which developmental windows are most vulnerable to MeCP2 disfunction remains unresolved. MeCP2 is a dosage-sensitive transcriptional regulator, whose functions are tightly linked to chromatin states. Because short-chain fatty acids (SCFAs) are known to inhibit histone deacetylases (HDACs), a tractable in vivo model is needed to test the effect of HDAC modulation on muscle defects. MethodsWe misexpressed human MECP2 in the Drosophila melanogaster mesoderm that gives rise to skeletal and visceral muscles. We analyzed quantitatively their morphology and function. To assess the effects of SCFA supplementation, we also supplemented diets with sodium butyrate (NaB), Lalbaay(R), a NaB-containing supplement, acetate (AcOH), and valproate (VPA). FindingsMECP2 misexpression caused pre-eclosion lethality, thinning of larval skeletal fibers with nuclear mispositioning and altered mitochondria. Functionally, it reduced locomotion, decreased food transit and gut peristalsis. Phenotypes were strongest when expression began during development. NaB and VPA supplementation rescue most of these phenotypes, consistent with their histone-deacetylase (HDAC) activity. Defects were not observed upon comparable misexpression of an RTT-associated MeCP2 loss-of-function variant, indicating that they might be relevant to pathogenesis of MECP2-related disorders. InterpretationOur genetic in vivo analysis models peripheral effects of MeCP2 dysregulation and their amelioration, supporting the possibility of HDAC-targeted strategies for MECP2-related muscle and gastrointestinal dysfunction.

genetics↗

bioRxiv2025

Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP

Enteroendocrine (EE) cells monitor the intestinal nutrient composition and consequently control organismal physiology through hormonal signaling. In addition to the immediate effects on hormone secretion, nutrients influence EE cell abundance by affecting the determination and maintenance of cell fate. EE cells are known to import and respond to dietary sugars, but how the sugar-induced changes in the intracellular metabolic state are sensed to control the immediate and long-term responses of EE cells, remains poorly understood. We report that the NADH binding transcriptional cofactor C-terminal binding protein (CtBP) acts at the interface between nutrient sensing and fate regulation of Drosophila larval EE cells, thus controlling organismal energy metabolism and survival on a high sugar diet. CtBP dimerization in EE cells is regulated through the redox balance of nicotinamide cofactors controlled by glycolysis and pentose phosphate pathway, allowing EE cells sense their internal metabolic state in response to sugar catabolism. CtBP interacts with the EE cell fate determining transcription factor Prospero through a conserved binding motif and binds to genomic targets controlling EE cell fate and size, such as components of Notch and insulin/mTOR pathways. Collectively, our findings uncover a modality where changes in intracellular redox state serve as an instructive signal to control EE cell function to globally control organismal homeostasis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/662346v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@3baaeorg.highwire.dtl.DTLVardef@d505edorg.highwire.dtl.DTLVardef@178361dorg.highwire.dtl.DTLVardef@128e210_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Sex-dependent neural plasticity in response to damage

Plasticity of intact adult neural tissue in the vicinity of neural damage serves to restore functionality of circuits. Much remains to be learned about the mechanisms regulating this process and the reported sex differences in recovery outcomes. Here, we present the fly gut and its innervation as a simplified model to address these questions. We show that gut damage caused by ingestion of toxic agents resulted in plasticity of the adult enteric neuronal network, manifested as a Reactive Oxygen Species (ROS)-dependent increase in neural tissue, which was reversible after a recovery period. Interestingly, males did not display neural plasticity, and masculinization of neurons in females suppressed the damage-dependent neural growth. Together, these findings position the fly gut as a system to investigate the cellular, molecular, and sex-specific underpinnings of neural plasticity, with implications for therapeutic advancements in neural circuit recovery. SUMMARY STATEMENTThis study establishes the fly gut as a simple system to explore how adult neural tissues differ between sexes in their capacity for plasticity.

neuroscience↗

bioRxiv2025

Intestinal control of feeding initiation in Drosophila melanogaster

The interplay between feeding and excretion is essential for organismal nutrition and survival, yet their mechanistic coupling remains poorly understood. At the onset of life, feeding must be initiated while developmental waste products - the meconium - need to be eliminated. Using Drosophila as a model system, we explored the in vivo mechanisms coordinating these processes. We developed novel behavioral assays for newly eclosed flies and discovered that, similar to neonatal mammals, Drosophila excrete their meconium shortly after eclosion. Remarkably, feeding initiation occurs only after partial meconium elimination. We identified a cis-regulatory element associated with the apterous gene, which, when disrupted, prevents both meconium excretion and adult feeding initiation. These flies develop hindgut obstruction (ileus), avoid food, and exhibit increased proboscis extension sleep - a behaviour we found plays a functional role in waste clearance under normal conditions. Through experimental inhibition of meconium excretion, we established that this process is prerequisite for feeding initiation, suggesting a gut-to-brain signaling circuit that couples these fundamental physiological processes. The progression of phenotypes we observed parallels the hallmarks of mechanical ileus in humans. Our findings reveal previously unrecognized links between intestinal clearance, feeding behavior, and survival, with potential implications for understanding similar processes across species.

developmental biology↗

bioRxiv2020

Discrete escape responses are generated by neuropeptide-mediated circuit logic

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.

neuroscience↗

bioRxiv2020

Female-specific upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity

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 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 in stunted, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination gene transformer regulates the diet-induced increase in stunted and 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.

physiology↗