-
Journal of Cell Science Jul 2023Neuronal dense-core vesicles (DCVs) contain neuropeptides and much larger proteins that affect synaptic growth and plasticity. Rather than using full collapse exocytosis...
Neuronal dense-core vesicles (DCVs) contain neuropeptides and much larger proteins that affect synaptic growth and plasticity. Rather than using full collapse exocytosis that commonly mediates peptide hormone release by endocrine cells, DCVs at the Drosophila neuromuscular junction release their contents via fusion pores formed by kiss-and-run exocytosis. Here, we used fluorogen-activating protein (FAP) imaging to reveal the permeability range of synaptic DCV fusion pores and then show that this constraint is circumvented by cAMP-induced extra fusions with dilating pores that result in DCV emptying. These Ca2+-independent full fusions require PKA-R2, a PKA phosphorylation site on Complexin and the acute presynaptic function of Rugose, the homolog of mammalian neurobeachin, a PKA-R2 anchor implicated in learning and autism. Therefore, localized Ca2+-independent cAMP signaling opens dilating fusion pores to release large cargoes that cannot pass through the narrower fusion pores that mediate spontaneous and activity-dependent neuropeptide release. These results imply that the fusion pore is a variable filter that differentially sets the composition of proteins released at the synapse by independent exocytosis triggers responsible for routine peptidergic transmission (Ca2+) and synaptic development (cAMP).
Topics: Animals; Synaptic Vesicles; Calcium; Synapses; Drosophila; Drosophila Proteins; Synaptic Transmission; Neuropeptides; Exocytosis; Membrane Fusion; Mammals
PubMed: 37303204
DOI: 10.1242/jcs.261026 -
Cell Reports Nov 2023In this study, we investigate the interplay between taste perception and macronutrients. While sugar's and protein's self-regulation of taste perception is known, the...
In this study, we investigate the interplay between taste perception and macronutrients. While sugar's and protein's self-regulation of taste perception is known, the role of fat remains unclear. We reveal that in Drosophila, fat overconsumption reduces fatty acid taste in favor of sweet perception. Conversely, sugar intake increases fatty acid perception and suppresses sweet taste. Genetic investigations show that the sugar signal, gut-secreted Hedgehog, suppresses sugar taste and enhances fatty acid perception. Fat overconsumption induces unpaired 2 (Upd2) secretion from adipose tissue to the hemolymph. We reveal taste neurons take up Upd2, which triggers Domeless suppression of fatty acid perception. We further show that the downstream JAK/STAT signaling enhances sweet perception and, via Socs36E, fine-tunes Domeless activity and the fatty acid taste perception. Together, our results show that sugar regulates Hedgehog signaling and fat induces Upd2 signaling to balance nutrient intake and to regulate sweet and fat taste perception.
Topics: Animals; Taste; Taste Perception; Drosophila; Sugars; Hedgehog Proteins; Carbohydrates; Drosophila Proteins; Adipose Tissue; Fatty Acids; Drosophila melanogaster
PubMed: 37934669
DOI: 10.1016/j.celrep.2023.113387 -
Epigenetics Dec 2023Ten-Eleven Translocation (TET) proteins have recently come to light as important epigenetic regulators conserved in multicellular organisms. TET knockdown studies in...
Ten-Eleven Translocation (TET) proteins have recently come to light as important epigenetic regulators conserved in multicellular organisms. TET knockdown studies in rodents have highlighted the critical role of these proteins for proper brain development and function. Mutations in mammalian mTET proteins and mTET2 specifically are frequent and deregulated in leukaemia and glioma respectively. Accordingly, we examined the role of mTET2 in tumorigenesis in larval haemocytes and adult heads in . Our findings showed that expression of mutant and wild type mTET2 resulted in general phenotypic defects in adult flies and accumulation of abdominal melanotic masses. Notably, flies with mTET2-R43G mutation at the N-terminus of mTET2 exhibited locomotor and circadian behavioural deficits, as well as reduced lifespan. Flies with mTET2-R1261C mutation in the catalytic domain, a common mutation in acute myeloid leukaemia (AML), displayed alterations affecting haemocyte haemostasis. Using transcriptomic approach, we identified upregulated immune genes in fly heads that were not exclusive to TET2 mutants but also found in wild type mTET2 flies. Furthermore, inhibiting expression of genes that were found to be deregulated in mTET2 mutants, such as those involved in immune pathways, autophagy, and transcriptional regulation, led to a rescue in fly survival, behaviour, and hemocyte number. This study identifies the transcriptomic profile of wild type mTET2 versus mTET2 mutants (catalytic versus non-catalytic) with indications of TET2 role in normal central nervous system (CNS) function and innate immunity.
Topics: Animals; Circadian Rhythm; DNA Methylation; Drosophila melanogaster; Drosophila Proteins; Gene Expression Profiling; Mammals; Mutation; Transcriptome; DNA-Binding Proteins; Dioxygenases
PubMed: 36989121
DOI: 10.1080/15592294.2023.2192375 -
EMBO Reports Sep 2023The ability of stem cells to switch between quiescent and proliferative states is crucial for maintaining tissue homeostasis and regeneration. Drosophila quiescent...
The ability of stem cells to switch between quiescent and proliferative states is crucial for maintaining tissue homeostasis and regeneration. Drosophila quiescent neural stem cells (qNSCs) extend a primary protrusion that is enriched in acentrosomal microtubules and can be regenerated upon injury. Arf1 promotes microtubule growth, reactivation (exit from quiescence), and regeneration of qNSC protrusions upon injury. However, how Arf1 is regulated in qNSCs remains elusive. Here, we show that the microtubule minus-end binding protein Patronin/CAMSAP promotes acentrosomal microtubule growth and quiescent NSC reactivation. Patronin is important for the localization of Arf1 at Golgi and physically associates with Arf1, preferentially with its GDP-bound form. Patronin is also required for the regeneration of qNSC protrusion, likely via the regulation of microtubule growth. Finally, Patronin functions upstream of Arf1 and its effector Msps/XMAP215 to target the cell adhesion molecule E-cadherin to NSC-neuropil contact sites during NSC reactivation. Our findings reveal a novel link between Patronin/CAMSAP and Arf1 in the regulation of microtubule growth and NSC reactivation. A similar mechanism might apply to various microtubule-dependent systems in mammals.
Topics: Animals; Microtubule-Associated Proteins; Drosophila; Microtubules; Drosophila Proteins; Neural Stem Cells; Mammals
PubMed: 37440685
DOI: 10.15252/embr.202256624 -
ELife Sep 2023Experiments on female fruit flies reveal more about the molecular mechanisms involved as germline stem cells transition to become egg cells.
Experiments on female fruit flies reveal more about the molecular mechanisms involved as germline stem cells transition to become egg cells.
Topics: Animals; Female; Drosophila melanogaster; Drosophila Proteins; Drosophila; Germ Cells; Stem Cells
PubMed: 37772961
DOI: 10.7554/eLife.91998 -
Pediatric Nephrology (Berlin, Germany) Dec 2023Biological and biomedical research using Drosophila melanogaster as a model organism has gained recognition through several Nobel prizes within the last 100 years.... (Review)
Review
Biological and biomedical research using Drosophila melanogaster as a model organism has gained recognition through several Nobel prizes within the last 100 years. Drosophila exhibits several advantages when compared to other in vivo models such as mice and rats, as its life cycle is very short, animal maintenance is easy and inexpensive and a huge variety of transgenic strains and tools are publicly available. Moreover, more than 70% of human disease-causing genes are highly conserved in the fruit fly. Here, we explain the use of Drosophila in nephrology research and describe two kidney tissues, Malpighian tubules and the nephrocytes. The latter are the homologous cells to mammalian glomerular podocytes and helped to provide insights into a variety of signaling pathways due to the high morphological similarities and the conserved molecular make-up between nephrocytes and podocytes. In recent years, nephrocytes have also been used to study inter-organ communication as links between nephrocytes and the heart, the immune system and the muscles have been described. In addition, other tissues such as the eye and the reproductive system can be used to study the functional role of proteins being part of the kidney filtration barrier.
Topics: Humans; Animals; Rats; Mice; Drosophila; Drosophila melanogaster; Drosophila Proteins; Kidney; Animals, Genetically Modified; Podocytes; Mammals
PubMed: 37171583
DOI: 10.1007/s00467-023-05996-w -
Trends in Biochemical Sciences Dec 2023The ability of neurites of the same neuron to avoid each other (self-avoidance) is a conserved feature in both invertebrates and vertebrates. The key to self-avoidance... (Review)
Review
The ability of neurites of the same neuron to avoid each other (self-avoidance) is a conserved feature in both invertebrates and vertebrates. The key to self-avoidance is the generation of a unique subset of cell-surface proteins in individual neurons engaging in isoform-specific homophilic interactions that drive neurite repulsion rather than adhesion. Among these cell-surface proteins are fly Dscam1 and vertebrate clustered protocadherins (cPcdhs), as well as the recently characterized shortened Dscam (sDscam) in the Chelicerata. Herein, we review recent advances in our understanding of how cPcdh, Dscam, and sDscam cell-surface recognition codes are expressed and translated into cellular functions essential for neural wiring.
Topics: Animals; Cell Adhesion Molecules; Cell Communication; Drosophila Proteins; Neurons; Protein Isoforms; Invertebrates; Vertebrates; Protocadherins
PubMed: 37839971
DOI: 10.1016/j.tibs.2023.09.001 -
The Journal of Cell Biology Jul 2023Regulated recruitment and activity of motor proteins is essential for intracellular transport of cargoes, including messenger ribonucleoprotein complexes (RNPs). Here,...
Regulated recruitment and activity of motor proteins is essential for intracellular transport of cargoes, including messenger ribonucleoprotein complexes (RNPs). Here, we show that orchestration of oskar RNP transport in the Drosophila germline relies on interplay between two double-stranded RNA-binding proteins, Staufen and the dynein adaptor Egalitarian (Egl). We find that Staufen antagonizes Egl-mediated transport of oskar mRNA by dynein both in vitro and in vivo. Following delivery of nurse cell-synthesized oskar mRNA into the oocyte by dynein, recruitment of Staufen to the RNPs results in dissociation of Egl and a switch to kinesin-1-mediated translocation of the mRNA to its final destination at the posterior pole of the oocyte. We additionally show that Egl associates with staufen (stau) mRNA in the nurse cells, mediating its enrichment and translation in the ooplasm. Our observations identify a novel feed-forward mechanism, whereby dynein-dependent accumulation of stau mRNA, and thus protein, in the oocyte enables motor switching on oskar RNPs by downregulating dynein activity.
Topics: Animals; Drosophila melanogaster; Drosophila Proteins; Dyneins; Kinesins; Oocytes; Ribonucleoproteins; RNA, Messenger; RNA-Binding Proteins; RNA Transport
PubMed: 37213090
DOI: 10.1083/jcb.202301113 -
Journal of Biological Rhythms Aug 2023Temperature influences animal physiology and behavior. Animals must set an appropriate body temperature to maintain homeostasis and maximize survival. Mammals set their... (Review)
Review
Temperature influences animal physiology and behavior. Animals must set an appropriate body temperature to maintain homeostasis and maximize survival. Mammals set their body temperatures using metabolic and behavioral strategies. The daily fluctuation in body temperature is called the body temperature rhythm (BTR). For example, human body temperature increases during wakefulness and decreases during sleep. BTR is controlled by the circadian clock, is closely linked with metabolism and sleep, and entrains peripheral clocks located in the liver and lungs. However, the underlying mechanisms of BTR are largely unclear. In contrast to mammals, small ectotherms, such as , control their body temperatures by choosing appropriate environmental temperatures. The preferred temperature of increases during the day and decreases at night; this pattern is referred to as the temperature preference rhythm (TPR). As flies are small ectotherms, their body temperature is close to that of the surrounding environment. Thus, TPR produces BTR, which exhibits a pattern similar to that of human BTR. In this review, we summarize the regulatory mechanisms of TPR, including recent studies that describe neuronal circuits relaying ambient temperature information to dorsal neurons (DNs). The neuropeptide diuretic hormone 31 (DH31) and its receptor (DH31R) regulate TPR, and a mammalian homolog of DH31R, the calcitonin receptor (CALCR), also plays an important role in mouse BTR regulation. In addition, both fly TPR and mammalian BTR are separately regulated from another clock output, locomotor activity rhythms. These findings suggest that the fundamental mechanisms of BTR regulation may be conserved between mammals and flies. Furthermore, we discuss the relationships between TPR and other physiological functions, such as sleep. The dissection of the regulatory mechanisms of TPR could facilitate an understanding of mammalian BTR and the interaction between BTR and sleep regulation.
Topics: Humans; Animals; Mice; Drosophila melanogaster; Temperature; Drosophila Proteins; Circadian Rhythm; Drosophila; Mammals
PubMed: 37222551
DOI: 10.1177/07487304231171624 -
Proceedings of the National Academy of... Oct 2023Sleep is vital for most animals, yet its mechanism and function remain unclear. We found that permeability of the BBB (blood-brain barrier)-the organ required for the...
Sleep is vital for most animals, yet its mechanism and function remain unclear. We found that permeability of the BBB (blood-brain barrier)-the organ required for the maintenance of homeostatic levels of nutrients, ions, and other molecules in the brain-is modulated by sleep deprivation (SD) and can cell-autonomously effect sleep changes. We observed increased BBB permeability in known sleep mutants as well as in acutely sleep-deprived animals. In addition to molecular tracers, SD-induced BBB changes also increased the penetration of drugs used in the treatment of brain pathologies. After chronic/genetic or acute SD, rebound sleep or administration of the sleeping aid gaboxadol normalized BBB permeability, showing that SD effects on the BBB are reversible. Along with BBB permeability, RNA levels of the BBB master regulator are modulated by sleep. Conversely, altering BBB permeability alone through glia-specific modulation of , or -each a well-studied regulator of BBB function-was sufficient to induce robust sleep phenotypes. These studies demonstrate a tight link between BBB permeability and sleep and indicate a unique role for the BBB in the regulation of sleep.
Topics: Animals; Blood-Brain Barrier; Drosophila; Sleep; Brain; Sleep Deprivation; Receptors, G-Protein-Coupled; Permeability; Drosophila Proteins
PubMed: 37831742
DOI: 10.1073/pnas.2309331120