Biology subjects

Gontijo, A. M.

Publications and source records attributed to Gontijo, A. M..

10 recordsLinked to original sources

bioRxiv2026

Ovary-Derived Signals Align Protein Appetite with Oogenesis

Maintaining organismal homeostasis requires mechanisms that coordinate the metabolic needs of individual organs with whole animal nutrient intake. Although nutrient sensors and central pathways regulating hunger have been extensively characterized, how peripheral organ physiology influences nutrient specific appetites remains poorly understood. Here, we identify a previously unrecognized signalling axis, originated in the ovary, that modulates yeast appetite in Drosophila melanogaster. Through a targeted germline RNAi screen, we find that specific perturbations in oogenesis consistently and selectively increase yeast appetite. The manipulations increasing yeast appetite disrupt oogenesis progression, producing a shared signature of increased vitellogenic follicle accumulation and reduced number of mature (stage14) oocytes. This shift is accompanied by decreased expression of the relaxin-like hormone Dilp8, and loss of Dilp8 recapitulates the feeding phenotype. We show that this ovarian regulation of nutrient specific appetite is independent of amino acid state but requires mating, indicating integration with Sex Peptide-mediated reproductive activation. Together, our findings uncover a novel mechanism that couples oogenesis progression to nutrient selection, emphasizing the importance of the ovary as an active regulator of whole organism nutritional decisions. This work provides a conceptual framework for how reproductive tissues communicate their physiological demands to other organs and raises the possibility that analogous ovary-derived signals may shape nutrient specific appetite and metabolic states in other animals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/711327v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@153c136org.highwire.dtl.DTLVardef@1b1e6dcorg.highwire.dtl.DTLVardef@abaab3org.highwire.dtl.DTLVardef@53f725_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Francisco, A. (2026) https://BioRender.com/pwalhtl

physiology↗

bioRxiv2025

Sex-specific control of locomotor behavior by neuronal Arhgef10 in aged Drosophila

Mutations and polymorphisms in the Rho guanine nucleotide exchange factor 10 (ARHGEF10) locus are associated with behavioral and locomotor dysfunctions in humans, including psychiatric disorders and polyneuropathies that show age- and sex-specific prevalence. ARHGEF10 encodes a conserved guanine exchange factor that activates Rho GTPases and has proposed roles in cell migration and adhesion, but the relevant cell types and mechanisms underlying its age- and sex-dependent effects remain unclear. Drosophila darhgef10 gene is the single orthologue of vertebrate ARHGEF10 and its paralogue ARHGEF10L. Here, to gain more direct insight into possible age- and sex-dependent ARHGEF10 neuromuscular functions, we generated darhgef10 knock-out flies and quantified induced walking kinematics with high-speed imaging and coarse spontaneous behaviors--walking, micromovements, rest, and sleep--in open arenas. Mutants of both sexes exhibited abnormal walking kinematics, which worsened with age in females. Cell-type-specific knockdowns indicated that locomotor phenotypes arose primarily from neuronal, rather than glial or muscle, requirements. dArhgef10 was especially critical in glutamatergic motor neurons of aged females. dArhgef10 was also required for wakefulness and activity initiation in females but, surprisingly, not in males. Genetic rescue and isoform expression analyses suggested that sexually-dimorphic expression of long isoforms RC and/or RD underlies at least part of the sex-specific requirements of dArhgef10 in locomotor behavior control, revealing unanticipated complexity in its activity regulation. Collectively, our results suggest ARHGEF10 plays an ancient, conserved role in neurons that promotes proper wakefulness and locomotor activity in an age- and sex-dependent manner.

animal behavior and cognition↗

bioRxiv2025

Relaxin signaling is critical for virgin female reproductive physiology in Drosophila

Ovulation enables mature oocytes to exit the ovary for potential fertilization. In Drosophila, ovulation is induced by mating but also occurs spontaneously in virgins, with rates varying widely in natural populations: short oocyte retention is ancestral, while longer retention is favored in colder climates. The molecular regulation of spontaneous ovulation remains unclear. Here, we show that disrupting the relaxin/insulin-like peptide Dilp8 or its receptor Lgr3--an orthologue of vertebrate RXFP1/2--in follicle cells or specific neurons, respectively, delays ovulation, slows average egg transit time in the reproductive tract, and facilitates oogenesis progression beyond [~]2 mature oocytes per ovariole, leading to mature follicle accumulation in the ovary. Mating largely rescues these defects, suggesting the pathway is dispensable post-mating. Dilp8-Lgr3 signaling ensures high oocyte quality by promoting elimination of lower-quality aging oocytes and by antagonizing oogenesis progression via an undefined mechanism downstream of Lgr3+ neurons. Our findings provide a molecular basis for oocyte retention time regulation in Drosophila involving ovarian-nervous system cross-talk, and bring further support for an ancient, conserved role for relaxin-like signaling in regulating ovulation and overall female reproductive physiology. Summary statementThis study uncovers how ovary-neuron communication promotes spontaneous ovulation and prevents buildup of aging eggs, ensuring optimal egg quality in fruit flies.

physiology↗

bioRxiv2024

Neurogenetic evidence for oscillatory behavior of Lgr3-positive growth control interneurons in Drosophila

The ability to achieve a species-specific size and proportion despite developmental or environmental perturbations is termed developmental stability. The molecular and cellular processes behind this are best understood in insects. In Drosophila, a peripheral-tissue stress signal, the relaxin/insulin-like peptide Dilp8, promotes developmental stability during larval development via its neuronal receptor, Lgr3, an ortholog of vertebrate relaxin receptors. Lgr3 signaling is widely accepted to occur in-and to activate (depolarize)-the central brain growth-coordinating interneurons (PIL/GCL neurons). Here, using neurogenetic approaches, we confirm the requirement of Lgr3 in PIL/GCL neurons, but unexpectedly find that they require both silenced (hyperpolarized) and active (depolarized) states for an appropriate response to Dilp8. These results are most simply explained if Lgr3 activation by Dilp8 triggers PIL/GCL-neuron oscillatory activity, and such oscillations promote developmental stability. PIL/GCL neurons express and require Cyclin A-which can form cell-cycle oscillator complexes with cyclin-dependent kinases-for their response to Dilp8, independently of Rca1 (regulator of CycA)/Emi1 (early mitotic inhibitor). This opens the possibility that cell-cycle machinery can be co-opted for postmitotic neuron oscillations, adding to an increasing list of postmitotic roles for cyclins. Neuroanatomically, we show that PIL/GCL neurons form reciprocally-innervating loops, which are common architectures in oscillating circuits and central pattern generators. The role of PIL/GCL neurons in developmental stability mirrors other homeostasis-regulating, peptide-driven oscillatory circuits found in the vertebrate hypothalamus, a developmentally-homologous region to the one occupied by PIL/GCL neurons in the fly brain.

neuroscience↗

bioRxiv2024

Non-gonadal PIWI protein, Aubergine, regulates regenerative stem cell proliferation and tumourigenesis in the Drosophila adult intestine.

The PIWI-interacting RNA (piRNA) biosynthesis pathway is best studied for its role suppressing Drosophila germline transposable elements. Piwi, the founding member of the pathway, is involved in adult intestinal stem cell (ISC) homeostasis. Whether a broader role of the PIWI pathway exists in the intestine, remains unknown. Here, we characterise a role of the PIWI family protein Aubergine (Aub) in ISCs. While dispensable for basal ISC self-renewal, upregulation of Aub by damage-induced reactive oxygen species drives regenerative ISC proliferation through increased protein synthesis, including translation of ISC factors Myc and Sox21a. Unexpectedly, such roles of Aub in ISCs appear uncoupled from its piRNA regulatory function. Additionally, Aub and mammalian PIWIL1, mediate tumorigenic intestinal growth in Drosophila and human organoids, respectively. Our results reveal regulated protein translation as a fundamental aspect of regenerative ISC function and discover a central role of Aub in such process.

developmental biology↗

bioRxiv2024

Drosophila Glue Expulsion and Spreading Behavior is Modulated by Neuropeptidergic Mip-SPR Signaling from a Descending Command Neuron

At the end of their growth phase, Drosophila larvae remodel their bodies, firmly glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process is termed pupariation and it is triggered by a surge in the steroid hormone ecdysone. Substrate attachment is achieved by a recently-described pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone after pupariation initiation is critical for unlocking progression of the pupariation motor program towards GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, we screened for such factors using cell type-specific RNA interference (RNAi) and behavioral monitoring. We identify Myoinhibiting peptide (Mip) and its highly conserved neuronal receptor, Sex peptide receptor (SPR), as a critical neuropeptidergic signaling pathway required to trigger and modulate multiple action components of GSB. In addition, we find that Mip is specifically required in a pair of descending neurons, whose optogenetic activation at a specific competence window triggers GSB-like behavior and whose neurogenetic silencing completely abrogates GSB without overtly affecting other pupariation components. This strongly suggests that these descending Mip neurons are developmentally-regulated GSB command neurons. Dissection of the GSB action components via muscle calcium-level monitoring coupled with cell-type specific RNAi indicates that Mip acts on multiple SPR-positive neuronal populations, which collectively define and pattern the sequence and timing of GSB actions. Hence, we have identified a pair of descending command neurons that utilize both synaptic transmission and neuropeptidergic signaling to trigger and modulate a complex innate behavior in Drosophila. Our results advance our molecular and cellular understanding of pupariation control, reveal the complexity of glue expulsion and spreading behavior control, provide insight into conserved aspects of Mip-SPR signaling in animals, and contribute to the understanding of how multi-step innate behaviors are coordinated in time and with other developmental processes through command neurons and neuropeptidergic signaling.

neuroscience↗

bioRxiv2022

marmite defines a novel conserved neuropeptide family mediating nutritional homeostasis

Neuropeptides play a key role in regulating physiology and behavior, including feeding. While animals modify their food choices to respond to the lack of specific nutrients, the mechanisms mediating nutrient-specific appetites remain unclear. Here, we identified marmite (mmt), a previously uncharacterized Drosophila melanogaster gene encoding a secreted peptide that controls feeding decisions. We show that both mmt mutants and neuronal knockdown of mmt specifically increased the intake of proteinaceous food, whereas neuronal mmt overexpression reduced protein appetite. mmt expression is also higher in animals maintained on amino acid rich food, suggesting that mmt encodes a protein-specific satiety signal. Mmt is expressed in a small number of neurons in the adult nervous system, with a single pair of neurons modulating protein appetite. Finally, sequence and phylogenetic analysis showed that mmt is part of an ancient and conserved family of neuropeptides, including the poorly understood vertebrate neuropeptides B and W genes. Functional experiments showed that mmt and vertebrate NPB and NPW modulate food intake in both flies and mice. Therefore, we discovered an ancient family of neuropeptides involved in controlling feeding across phyla.

neuroscience↗

bioRxiv2020

Innate behavior sequence progression by peptide-mediated interorgan crosstalk

Innate behaviors consist of a succession of genetically-hardwired motor and physiological subprograms that can be coupled to drastic morphogenetic changes. How these integrative responses are orchestrated is not completely understood. Here, we provide insight into these mechanisms by studying pupariation, a multi-step innate behavior of fly larvae that is critical for survival during metamorphosis. We find that the steroid-hormone ecdysone triggers parallel pupariation neuromotor and morphogenetic subprograms, which include the induction of the relaxin-peptide hormone, Dilp8, in the epidermis. Dilp8 acts on six Lgr3-positive thoracic interneurons to couple both subprograms in time and to instruct neuromotor subprogram switching during behavior. Our work reveals that interorgan feedback gates progression between subunits of an innate behavior and points to an ancestral neuromodulatory function of relaxin signaling.

animal behavior and cognition↗

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↗

bioRxiv2019

The intersectional genetics landscape for human

The human body is made up of hundreds, perhaps thousands of cell types and states, most of which are currently inaccessible genetically. Genetic accessibility carries significant diagnostic and therapeutic potential by allowing the selective delivery of genetic messages or cures to cells. Research in model organisms has shown that single regulatory element (RE) activities are seldom cell type specific, limiting their usage in genetic systems designed to restrict gene expression posteriorly to their delivery to cells. Intersectional genetic approaches can increase the number of genetically accessible cells. A typical intersectional method acts like an AND logic gate by converting the input of two or more active REs into a single synthetic output, which becomes unique for that cell. Here, we systematically assessed the intersectional genetics landscape of human using a curated subset of cells from a large RE usage atlas obtained by Cap Analysis of Gene Expression Sequencing (CAGE-Seq) of thousands of primary and cancer cells (the FANTOM5 consortium atlas). We developed the heuristics and algorithms to retrieve and quality rank AND gate intersections intra- and inter-individually. We find that >90% of the 154 primary cell types surveyed can be distinguished from each other with as little as 3 to 4 active REs, with quantifiable safety and robustness. We call these minimal intersections of active REs with cell-type diagnostic potential "Versatile Entry Codes" (VEnCodes). We show that VEnCodes could be found for 100% of the 158 cancer cell types surveyed, and that most of these are highly robust to intra- and interindividual variation. Our tools for generating and quality-ranking VEnCodes can be adapted to other RE usage databases and to other intersectional methods using alternative Boolean logic operations. Our work demonstrate the potential of intersectional approaches for future gene delivery technologies in human.

bioinformatics↗