System-wide mapping of peptide-GPCR interactions in C. elegans

Cell Reports, Год журнала: 2023, Номер 42(9), С. 113058 - 113058

Опубликована: Авг. 31, 2023

Neuropeptides and peptide hormones are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of peptidergic network roles many peptides remain elusive, as our insight into peptide-receptor interactions is limited GPCRs still orphan receptors. Here we report genome-wide peptide-GPCR interaction map in Caenorhabditis elegans. By reverse pharmacology screening over 55,384 possible interactions, identify 461 cognate couples uncover with specific complex combinatorial encoded across within single genes. These provide insights functions evolution. Combining dataset phylogenetic analysis supports co-evolution conservation at least 14 bilaterian systems C. This resource lays foundation for system-wide network.

Язык: Английский

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Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse

Cell Research, Год журнала: 2023, Номер 33(6), С. 434 - 447

Опубликована: Апрель 13, 2023

Abstract Obesity imposes a global health threat and calls for safe effective therapeutic options. Here, we found that protein-rich diet significantly reduced body fat storage in fruit flies, which was largely attributed to dietary cysteine intake. Mechanistically, increased the production of neuropeptide FMRFamide (FMRFa). Enhanced FMRFa activity simultaneously promoted energy expenditure suppressed food intake through its cognate receptor (FMRFaR), both contributing loss effect. In body, signaling lipolysis by increasing PKA lipase activity. sweet-sensing gustatory neurons, appetitive perception hence We also demonstrated worked similar way mice via FF (NPFF) signaling, mammalian RFamide peptide. addition, or FMRFa/NPFF administration provided protective effect against metabolic stress flies without behavioral abnormalities. Therefore, our study reveals novel target development therapies obesity related diseases.

Язык: Английский

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Synaptic connectome of theDrosophilacircadian clock

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 13, 2023

The circadian clock and its output pathways play a pivotal role in optimizing daily processes. To obtain novel insights into how diverse rhythmic physiology behaviors are orchestrated, we have generated the first comprehensive connectivity map of an animal using Drosophila FlyWire brain connectome. Intriguingly, identified additional dorsal neurons, thus showing that network contains ∼240 instead 150 neurons. We also revealed extensive contralateral synaptic within discovered indirect light input to Interestingly, observed sparse monosynaptic between neurons down-stream higher-order centers neurosecretory cells known regulate behavior physiology. Therefore, integrated single-cell transcriptomics receptor mapping decipher putative paracrine peptidergic signaling by Our analyses neuropeptides expressed suggest significantly enriches interconnectivity network.

Язык: Английский

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Synaptic connectome of the Drosophila circadian clock

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Дек. 5, 2024

Abstract The circadian clock and its output pathways play a pivotal role in optimizing daily processes. To obtain insights into how diverse rhythmic physiology behaviors are orchestrated, we have generated comprehensive connectivity map of an animal using the Drosophila FlyWire brain connectome. Intriguingly, identified additional dorsal neurons, thus showing that network contains ~240 instead 150 neurons. We revealed extensive contralateral synaptic within discovered novel indirect light input to also elucidated via which modulates descending neurons known regulate feeding reproductive behaviors. Interestingly, observed sparse monosynaptic between downstream higher-order centers neurosecretory cells behavior physiology. Therefore, integrated single-cell transcriptomics receptor mapping decipher putative paracrine peptidergic signaling by Our analyses neuropeptides expressed suggest significantly enriches interconnectivity network.

Язык: Английский

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Aminergic and peptidergic modulation of Insulin-Producing Cells in Drosophila

Опубликована: Фев. 10, 2025

Insulin plays a critical role in maintaining metabolic homeostasis. Since demands are highly dynamic, insulin release needs to be constantly adjusted. These adjustments mediated by different pathways, most prominently the blood glucose level, but also feedforward signals from motor circuits and neuromodulatory systems. Here, we analyze how inputs control activity of main source Drosophila – population Insulin-Producing Cells (IPCs) located brain. IPCs functionally analogous mammalian pancreatic beta cells, their location makes them accessible for vivo recordings intact animals. We characterized functional using single-nucleus RNA sequencing analysis, anatomical receptor expression mapping, connectomics, an optogenetics-based ‘intrinsic pharmacology’ approach. Our results show that IPC expresses variety receptors neuromodulators classical neurotransmitters. Interestingly, exhibit heterogeneous profiles, suggesting can modulated differentially. This is supported electrophysiological IPCs, which performed while activating populations modulatory neurons. analysis revealed some have effects on activity, such they inhibit one subset exciting another. Monitoring calcium across uncovered these responses occur simultaneously. Certain shifted towards excited state, others it inhibition. Taken together, provide comprehensive, multi-level neuromodulation insulinergic system .

Язык: Английский

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Network Statistics of the Whole-Brain Connectome ofDrosophila

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 29, 2023

Abstract Brains comprise complex networks of neurons and connections. Network analysis applied to the wiring diagrams brains can offer insights into how support computations regulate information flow. The completion first whole-brain connectome an adult Drosophila , largest date, containing 130,000 millions connections, offers unprecedented opportunity analyze its network properties topological features. To gain local connectivity, we computed prevalence two- three-node motifs, examined their strengths neurotransmitter compositions, compared these metrics with other animals. We discovered that fly brain displays rich club organization, a large population (30% percent connectome) highly connected neurons. identified subsets may serve as integrators or broadcasters signals. Finally, subnetworks based on 78 anatomically defined regions neuropils. These data products are shared within FlyWire Codex will foundation for models experiments exploring relationship between neural activity anatomical structure.

Язык: Английский

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Aminergic and peptidergic modulation of Insulin-Producing Cells in Drosophila

Опубликована: Сен. 10, 2024

Insulin plays a critical role in maintaining metabolic homeostasis. Since demands are highly dynamic, insulin release needs to be constantly adjusted. These adjustments mediated by different pathways, most prominently the blood glucose level, but also feedforward signals from motor circuits and neuromodulatory systems. Here, we analyze how inputs control activity of main source Drosophila – population Insulin-Producing Cells (IPCs) located brain. IPCs functionally analogous mammalian pancreatic beta cells, their location makes them accessible for vivo recordings intact animals. We characterized functional using single-nucleus RNA sequencing analysis, anatomical receptor expression mapping, connectomics, an optogenetics-based ‘in-trinsic pharmacology’ approach. Our results show that IPC expresses variety receptors neuromodulators classical neurotransmitters. Interestingly, exhibit heterogeneous profiles, suggesting can modulated differentially. This is supported electrophysiological IPCs, which performed while activating populations modulatory neurons. analysis revealed some have effects on activity, such they inhibit one subset exciting another. Monitoring calcium across uncovered these responses occur simultaneously. Certain shifted towards excited state, others it inhibition. Taken together, provide comprehensive, multi-level neuromodulation insulinergic system .

Язык: Английский

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Synaptic connectome of a neurosecretory network in the Drosophila brain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 29, 2024

Abstract Hormones mediate inter-organ signaling which is crucial in orchestrating diverse behaviors and physiological processes including sleep activity, feeding, growth, metabolism reproduction. The pars intercerebralis lateralis insects represent major hubs contain neurosecretory cells (NSC) that produce various hormones. To obtain insight into how hormonal regulated, we have characterized the synaptic connectome of NSC adult Drosophila brain. Identification neurons providing inputs to multiple subtypes implicates diuretic hormone 44-expressing as a coordinator physiology behavior. Surprisingly, despite most having dendrites subesophageal zone (primary taste processing center), gustatory are largely indirect. We also deciphered pathways via olfactory relayed NSC. Further, our analyses revealed substantial from descending NSC, suggesting regulate both endocrine motor output synchronize changes with appropriate behaviors. In contrast inputs, sparse mostly mediated by corazonin Therefore, additionally determine putative paracrine interconnectivity between peripheral tissues analyzing single-cell transcriptomic datasets. Our comprehensive characterization network provides platform understand complex networks they orchestrate animal physiology.

Язык: Английский

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System-wide mapping of neuropeptide-GPCR interactions inC. elegans

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Ноя. 1, 2022

Summary Neuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of peptidergic network and roles many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited peptide GPCRs in animal models humans still orphan receptors. Here we report genome-wide neuropeptide-GPCR interaction map C. elegans . By reverse pharmacology screening over 55,384 possible interactions, identify 461 cognate peptide-GPCR couples uncover with specific complex combinatorial encoded across within single genes. These provide insights neuropeptide functions evolution. Combining dataset phylogenetic analysis supports peptide-receptor co-evolution conservation at least 14 bilaterian systems This resource lays foundation for system-wide network. Highlights System-wide deorphanizes 68 Discovery pairs additional ligands characterized show receptor Peptide-GPCR support long-range expansion

Язык: Английский

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Hunger- and thirst-sensing neurons modulate a neuroendocrine network to coordinate sugar and water ingestion

eLife, Год журнала: 2023, Номер 12

Опубликована: Июнь 15, 2023

Consumption of food and water is tightly regulated by the nervous system to maintain internal nutrient homeostasis. Although generally considered independently, interactions between hunger thirst drives are important coordinate competing needs. In Drosophila , four neurons called interoceptive subesophageal zone (ISNs) respond intrinsic signals oppositely regulate sucrose ingestion. Here, we investigate neural circuit downstream ISNs examine how ingestion based on Utilizing recently available fly brain connectome, find that synapse with a novel cell-type bilateral T-shaped neuron (BiT) projects neuroendocrine centers. vivo manipulations revealed BiT regulates sugar Neuroendocrine cells include several peptide-releasing peptide-sensing neurons, including insulin producing (IPCs), crustacean cardioactive peptide (CCAP) CCHamide-2 receptor isoform RA (CCHa2R-RA) neurons. These contribute differentially water, IPCs CCAP regulating ingestion, CCHa2R-RA modulating only Thus, decision consume or occurs via regulation broad peptidergic network integrates nutritional state generate nutrient-specific

Язык: Английский

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