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1.
Pestic Biochem Physiol ; 187: 105177, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36127041

RESUMO

Insect nicotinic acetylcholine receptors (nAChRs) require cofactors for functional heterologous expression. A previous study revealed that TMX3 was crucial for the functional expression of Drosophila melanogaster Dα1/Dß1 nAChRs in Xenopus laevis oocytes, while UNC-50 and RIC-3 enhanced the acetylcholine (ACh)-induced responses of the nAChRs. However, it is unclear whether the coexpression of UNC-50 and RIC-3 with TMX3 and the subunit stoichiometry affect pharmacology of Dα1/Dß1 nAChRs when expressed in X. laevis oocytes. We have investigated the effects of coexpressing UNC-50 and RIC-3 with TMX3 as well as changing the subunit stoichiometry on the agonist activity of ACh and imidacloprid on the Dα1/Dß1 nAChRs. UNC-50 and RIC-3 hardly affected the agonist affinity of ACh and imidacloprid for the Dα1/Dß1 nAChRs formed by injecting into X. laevis oocytes with an equal amount mixture of the subunit cRNAs, but enhanced current amplitude of the ACh-induced response. Imidacloprid showed higher affinity for the Dß1 subunit-excess Dα1/Dß1 (Dα1/Dß1 = 1/5) nAChRs than the Dα1 subunit-excess Dα1/Dß1 (Dα1/Dß1 = 5/1) nAChRs, suggesting that imidacloprid prefers the Dα1-Dß1 orthosteric site over the Dα1-Dα1 orthosteric site.


Assuntos
Receptores Nicotínicos , Acetilcolina/farmacologia , Animais , Drosophila melanogaster/metabolismo , Neonicotinoides , Nitrocompostos , Oócitos/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Xenopus laevis/metabolismo , Proteínas ras/metabolismo , Proteínas ras/farmacologia
2.
BMC Genomics ; 23(1): 641, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36076188

RESUMO

BACKGROUND: Maternal gene products supplied to the egg during oogenesis drive the earliest events of development in all metazoans. After the initial stages of embryogenesis, maternal transcripts are degraded as zygotic transcription is activated; this is known as the maternal to zygotic transition (MZT). Recently, it has been shown that the expression of maternal and zygotic transcripts have evolved in the Drosophila genus over the course of 50 million years. However, the extent of natural variation of maternal and zygotic transcripts within a species has yet to be determined. We asked how the maternal and zygotic pools of mRNA vary within and between populations of D. melanogaster. In order to maximize sampling of genetic diversity, African lines of D. melanogaster originating from Zambia as well as DGRP lines originating from North America were chosen for transcriptomic analysis. RESULTS: Generally, we find that maternal transcripts are more highly conserved, and zygotic transcripts evolve at a higher rate. We find that there is more within-population variation in transcript abundance than between populations and that expression variation is highest post- MZT between African lines. CONCLUSIONS: Determining the natural variation of gene expression surrounding the MZT in natural populations of D. melanogaster gives insight into the extent of how a tightly regulated process may vary within a species, the extent of developmental constraint at both stages and on both the maternal and zygotic genomes, and reveals expression changes allowing this species to adapt as it spread across the world.


Assuntos
Drosophila melanogaster , Regulação da Expressão Gênica no Desenvolvimento , Animais , Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Desenvolvimento Embrionário/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Zigoto/metabolismo
3.
Philos Trans R Soc Lond B Biol Sci ; 377(1862): 20210288, 2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36058243

RESUMO

The visual pigments known as opsins are the primary molecular basis for colour vision in animals. Insects are among the most diverse of animal groups and their visual systems reflect a variety of life histories. The study of insect opsins in the fruit fly Drosophila melanogaster has led to major advances in the fields of neuroscience, development and evolution. In the last 25 years, research in D. melanogaster has improved our understanding of opsin genotype-phenotype relationships while comparative work in other insects has expanded our understanding of the evolution of insect eyes via gene duplication, coexpression and homologue switching. Even so, until recently, technology and sampling have limited our understanding of the fundamental mechanisms that evolution uses to shape the diversity of insect eyes. With the advent of genome editing and in vitro expression assays, the study of insect opsins is poised to reveal new frontiers in evolutionary biology, visual neuroscience, and animal behaviour. This article is part of the theme issue 'Understanding colour vision: molecular, physiological, neuronal and behavioural studies in arthropods'.


Assuntos
Drosophila melanogaster , Opsinas , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Evolução Molecular , Insetos/genética , Insetos/metabolismo , Opsinas/genética , Opsinas/metabolismo , Filogenia
4.
PLoS Genet ; 18(9): e1010385, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36070313

RESUMO

Stem cells are essential for the development and long-term maintenance of tissues and organisms. Preserving tissue homeostasis requires exquisite control of all aspects of stem cell function: cell potency, proliferation, fate decision and differentiation. RNA binding proteins (RBPs) are essential components of the regulatory network that control gene expression in stem cells to maintain self-renewal and long-term homeostasis in adult tissues. While the function of many RBPs may have been characterized in various stem cell populations, how these interact and are organized in genetic networks remains largely elusive. In this report, we show that the conserved RNA binding protein IGF2 mRNA binding protein (Imp) is expressed in intestinal stem cells (ISCs) and progenitors in the adult Drosophila midgut. We demonstrate that Imp is required cell autonomously to maintain stem cell proliferative activity under normal epithelial turnover and in response to tissue damage. Mechanistically, we show that Imp cooperates and directly interacts with Lin28, another highly conserved RBP, to regulate ISC proliferation. We found that both proteins bind to and control the InR mRNA, a critical regulator of ISC self-renewal. Altogether, our data suggests that Imp and Lin28 are part of a larger gene regulatory network controlling gene expression in ISCs and required to maintain epithelial homeostasis.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Intestinos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais
5.
Cell Death Dis ; 13(9): 756, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056003

RESUMO

In Drosophila ovary, niche is composed of somatic cells, including terminal filament cells (TFCs), cap cells (CCs) and escort cells (ECs), which provide extrinsic signals to maintain stem cell renewal or initiate cell differentiation. Niche establishment begins in larval stages when terminal filaments (TFs) are formed, but the underlying mechanism for the development of TFs remains largely unknown. Here we report that transcription factor longitudinals lacking (Lola) is essential for ovary morphogenesis. We showed that Lola protein was expressed abundantly in TFCs and CCs, although also in other cells, and lola was required for the establishment of niche during larval stage. Importantly, we found that knockdown expression of lola induced apoptosis in adult ovary, and that lola affected adult ovary morphogenesis by suppressing expression of Regulator of cullins 1b (Roc1b), an apoptosis-related gene that regulates caspase activation during spermatogenesis. These findings significantly expand our understanding of the mechanisms controlling niche establishment and adult oogenesis in Drosophila.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Apoptose/genética , Diferenciação Celular/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Masculino , Ovário/metabolismo , Nicho de Células-Tronco/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
PLoS Genet ; 18(9): e1010371, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36048889

RESUMO

The regulation of ribosome function is a conserved mechanism of growth control. While studies in single cell systems have defined how ribosomes contribute to cell growth, the mechanisms that link ribosome function to organismal growth are less clear. Here we explore this issue using Drosophila Minutes, a class of heterozygous mutants for ribosomal proteins. These animals exhibit a delay in larval development caused by decreased production of the steroid hormone ecdysone, the main regulator of larval maturation. We found that this developmental delay is not caused by decreases in either global ribosome numbers or translation rates. Instead, we show that they are due in part to loss of Rp function specifically in a subset of serotonin (5-HT) neurons that innervate the prothoracic gland to control ecdysone production. We find that these effects do not occur due to altered protein synthesis or proteostasis, but that Minute animals have reduced expression of synaptotagmin, a synaptic vesicle protein, and that the Minute developmental delay can be partially reversed by overexpression of synaptic vesicle proteins in 5-HTergic cells. These results identify a 5-HT cell-specific role for ribosomal function in the neuroendocrine control of animal growth and development.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ecdisona/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Larva , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/genética , Serotonina/metabolismo
7.
BMC Biol ; 20(1): 198, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071487

RESUMO

BACKGROUND: Drosophila melanogaster lipophorin receptors (LpRs), LpR1 and LpR2, are members of the LDLR family known to mediate lipid uptake in a range of organisms from Drosophila to humans. The vertebrate orthologs of LpRs, ApoER2 and VLDL-R, function as receptors of a glycoprotein involved in development of the central nervous system, Reelin, which is not present in flies. ApoER2 and VLDL-R are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain, as well as with neurodevelopmental and neurodegenerative disorders linked to those regions. It is currently unknown whether LpRs play similar roles in the Drosophila brain. RESULTS: We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the mushroom bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurite arborization. This effect depends on LpRs and Dab, the Drosophila ortholog of the Reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin, suggesting that Drosophila LpRs interact with human Reelin to induce downstream cellular events. CONCLUSIONS: These findings demonstrate that LpRs contribute to MB development and function, supporting the existence of a LpR-dependent signaling in Drosophila, and advance our understanding of the molecular factors functioning in neural systems to generate complex behaviors in this model. Our results further emphasize the importance of Drosophila as a model to investigate the alterations in specific genes contributing to neural disorders.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Corpos Pedunculados , Receptores Citoplasmáticos e Nucleares , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/farmacologia , Corpos Pedunculados/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína Reelina , Serina Endopeptidases/metabolismo
8.
Elife ; 112022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36083801

RESUMO

The oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO) is a key transducer of the hedgehog (HH) morphogen, which plays an essential role in the patterning of epithelial structures. Here, we examine how HH controls SMO subcellular localization and activity in a polarized epithelium using the Drosophila wing imaginal disc as a model. We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of protein kinase A, casein kinase I, and the Fused (FU) kinase. Moreover, in the presence of very high levels of HH, the second effect of FU leads to the local enrichment of SMO in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of HH to the apico-basal distribution of SMO and provide a novel mechanism for the regulation of a GPCR.


Assuntos
Proteínas de Drosophila , Proteínas Hedgehog , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas Hedgehog/metabolismo , Fosforilação , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismo
9.
Nat Commun ; 13(1): 5006, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008386

RESUMO

The dynamics and connectivity of neural circuits continuously change on timescales ranging from milliseconds to an animal's lifetime. Therefore, to understand biological networks, minimally invasive methods are required to repeatedly record them in behaving animals. Here we describe a suite of devices that enable long-term optical recordings of the adult Drosophila melanogaster ventral nerve cord (VNC). These consist of transparent, numbered windows to replace thoracic exoskeleton, compliant implants to displace internal organs, a precision arm to assist implantation, and a hinged stage to repeatedly tether flies. To validate and illustrate our toolkit we (i) show minimal impact on animal behavior and survival, (ii) follow the degradation of chordotonal organ mechanosensory nerve terminals over weeks after leg amputation, and (iii) uncover waves of neural activity caffeine ingestion. Thus, our long-term imaging toolkit opens up the investigation of premotor and motor circuit adaptations in response to injury, drug ingestion, aging, learning, and disease.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Comportamento Animal , Diagnóstico por Imagem , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo
10.
Gene ; 845: 146832, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36007803

RESUMO

Polycomb and Trithorax group proteins (PcG, TrxG) epigenetically regulate developmental genes. These proteins bind with specific DNA elements, the Polycomb Response Element (PRE). Apart from mutations in polycomb/ trithorax proteins, altered cis-elements like PRE underlie the modified function and thus disease etiology. PREs are well studied in Drosophila, while only a few human PREs have been reported. We have identified a polycomb responsive DNA element, hPRE-HoxA3, in the intron of the HoxA3 gene. The hPRE-HoxA3 represses luciferase reporter activity in a PcG-dependent manner. The endogenous hPRE-HoxA3 element recruits PcG proteins and is enriched with repressive H3K27me3 marks, demonstrating that hPRE-HoxA3 is a part of the PcG-dependent gene regulatory network. Furthermore, it interacts with D11-12, the well-known PRE in the human Hox cluster. hPRE-Hox3 is a part of the 3-dimensional chromosomal domain organization as it is involved in the long-range interaction with other PcG enriched regions of Hox A, B, C, and D clusters.


Assuntos
Proteínas de Drosophila , Histonas , Animais , Drosophila/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Genômica , Histonas/genética , Histonas/metabolismo , Humanos , Luciferases/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Elementos de Resposta , Fatores de Transcrição/genética
11.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35955662

RESUMO

Memories are lasting representations over time of associations between stimuli or events. In general, the relatively slow consolidation of memories requires protein synthesis with a known exception being the so-called Anesthesia Resistant Memory (ARM) in Drosophila. This protein synthesis-independent memory type survives amnestic shocks after a short, sensitive window post training, and can also emerge after repeated cycles of training in a negatively reinforced olfactory conditioning task, without rest between cycles (massed conditioning-MC). We discussed operational and molecular mechanisms that mediate ARM and differentiate it from protein synthesis-dependent long-term memory (LTM) in Drosophila. Based on the notion that ARM is unlikely to specifically characterize Drosophila, we examined protein synthesis and MC-elicited memories in other species and based on intraspecies shared molecular components and proposed potential relationships of ARM with established memory types in Drosophila and vertebrates.


Assuntos
Anestesia , Proteínas de Drosophila , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Memória , Memória de Longo Prazo
12.
Int J Mol Sci ; 23(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35955923

RESUMO

A systematic investigation on the cellular uptake, intracellular dissolution, and in vitro biological effects of ultra-small (<10 nm) iron hydroxide adipate/tartrate coated nanoparticles (FeAT-NPs) was carried out in intestinal Caco-2, hepatic HepG2 and ovarian A2780 cells, and the nucleotide excision repair (NER) deficient GM04312 fibroblasts. Quantitative evaluation of the nanoparticles uptake, as well as their transformation within the cell cytosol, was performed by inductively coupled plasma mass spectrometry (ICP-MS), alone or in combination with high performance liquid chromatography (HPLC). The obtained results revealed that FeAT-NPs are effectively taken up in a cell type-dependent manner with a minimum dissolution after 3 h. These results correlated with no effects on cell proliferation and minor effects on cell viability and reactive oxygen species (ROS) production for all the cell lines under study. Moreover, the comet assay results revealed significant DNA damage only in GM04312 cells. In vivo genotoxicity was further studied in larvae from Drosophila melanogaster, using the eye-SMART test. The obtained results showed that FeAT-NPs were genotoxic only with the two highest tested concentrations (2 and 5 mmol·L-1 of Fe) in surface treatments. These data altogether show that these nanoparticles represent a safe alternative for anemia management, with high uptake level and controlled iron release.


Assuntos
Nanopartículas , Neoplasias Ovarianas , Animais , Biotransformação , Células CACO-2 , Linhagem Celular Tumoral , Sobrevivência Celular , Dano ao DNA , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Humanos , Ferro/farmacologia , Larva/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo
13.
Cell Rep ; 40(8): 111263, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36001962

RESUMO

In animal germlines, transposons are silenced at the transcriptional or post-transcriptional level to prevent deleterious expression. Ciliates employ a more direct approach by physically eliminating transposons from their soma, utilizing piRNAs to recognize transposons and imprecisely excise them. Ancient, mutated transposons often do not require piRNAs and are precisely eliminated. Here, we characterize the Polycomb Repressive Complex 2 (PRC2) in Paramecium and demonstrate its involvement in the removal of transposons and transposon-derived DNA. Our results reveal a striking difference between the elimination of new and ancient transposons at the chromatin level and show that the complex may be guided by Piwi-bound small RNAs (sRNAs). We propose that imprecise elimination in ciliates originates from an ancient transposon silencing mechanism, much like in plants and metazoans, through sRNAs, repressive methylation marks, and heterochromatin formation. However, it is taken a step further by eliminating DNA as an extreme form of transposon silencing.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Animais , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , DNA/metabolismo , Elementos de DNA Transponíveis/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Inativação Gênica , Complexo Repressor Polycomb 2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
14.
Proc Natl Acad Sci U S A ; 119(32): e2204779119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914128

RESUMO

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.


Assuntos
Azauridina , Proteína Huntingtina , Doença de Huntington , Proteínas Mutantes , Mutação , Proteínas Nucleares , Fenótipo , Proteínas Repressoras , Fatores de Elongação da Transcrição , Alelos , Animais , Azauridina/farmacologia , Células Cultivadas , Expansão das Repetições de DNA , Modelos Animais de Doenças , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Proteína Huntingtina/biossíntese , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Medições Luminescentes , Proteínas Mutantes/biossíntese , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Nucleares/metabolismo , Células Fotorreceptoras de Invertebrados/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Fatores de Elongação da Transcrição/metabolismo
15.
Proc Natl Acad Sci U S A ; 119(32): e2208317119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914137

RESUMO

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.


Assuntos
AMP Cíclico , Proteínas de Drosophila , Drosophila melanogaster , Estresse do Retículo Endoplasmático , Nucleotidiltransferases , Estresse Fisiológico , Resposta a Proteínas não Dobradas , Alelos , Animais , AMP Cíclico/metabolismo , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Nucleotidiltransferases/deficiência , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Estresse Fisiológico/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
16.
Aging (Albany NY) ; 14(16): 6427-6448, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35980274

RESUMO

Food has a decisive influence on our health, to the extent where even lifespan can be directly affected by it. In the present work, we have examined the effects of an aqueous extract of the marine brown alga Eisenia bicyclis in terms of its potential to extend lifespan. For this purpose, we used the fruit fly Drosophila melanogaster as a model. The experiments showed that small amounts of Eisenia extract can extend lifespan by up to 40%. This effect is not only related to the median but also to the maximum lifespan. Interestingly, this life-extending effect is sex-specific, i.e. it occurs exclusively in females. Even under stressful nutritional conditions such as a high sugar diet, this effect is detectable. Mechanistic studies showed that this life-prolonging effect depends on a functional Tor and a functional FoxO signaling pathway. It can be concluded that components of the Eisenia extract prolong lifespan by interacting with the Tor-FoxO axis. This study may serve to stimulate further investigations, which on the one hand show such a life-prolonging effect also in other organisms and on the other hand identify the substances responsible for this effect. Finally, it may also encourage the increased use of arame as a health-promoting food supplement.


Assuntos
Proteínas de Drosophila , Feófitas , Animais , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Fatores de Transcrição Forkhead , Longevidade , Masculino , Feófitas/metabolismo , Proteínas
17.
J Cell Sci ; 135(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35950520

RESUMO

Deltex (Dx) is a context-dependent regulator of Notch signaling that can act in a non-canonical fashion by facilitating the endocytosis of the Notch receptor. In an RNAi-based modifier screen of kinases and phosphatases, we identified Thickveins (Tkv), the receptor of Decapentaplegic (Dpp), as one of the interactors of Dx. Dpp, a Drosophila homolog of TGF-ß and bone morphogenetic proteins, acts as a morphogen to specify cell fate along the anterior-posterior axis of the wing. Tight regulation of Dpp signaling is thus indispensable for its proper functioning. Here, we present Dx as a novel modulator of Dpp signaling. We show evidence for the very first time that dx genetically interacts with dpp and its pathway components. Immunocytochemical analysis revealed that Dx colocalizes with Dpp and its receptor Tkv in Drosophila third-instar larval tissues. Furthermore, Dx was also seen to modulate the expression of dpp and its target genes, and we attribute this modulation to the involvement of Dx in the endocytosis and trafficking of Dpp. This study thus presents a whole new avenue of Dpp signaling regulation via the cytoplasmic protein Dx. This article has an associated First Person interview with the first author of the paper.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Serina-Treonina Quinases/genética , Receptores de Superfície Celular/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Asas de Animais
18.
Elife ; 112022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36040415

RESUMO

Temporal patterning is an important mechanism for generating a great diversity of neuron subtypes from a seemingly homogenous progenitor pool in both vertebrates and invertebrates. Drosophila neuroblasts are temporally patterned by sequentially expressed Temporal Transcription Factors (TTFs). These TTFs are proposed to form a transcriptional cascade based on mutant phenotypes, although direct transcriptional regulation between TTFs has not been verified in most cases. Furthermore, it is not known how the temporal transitions are coupled with the generation of the appropriate number of neurons at each stage. We use neuroblasts of the Drosophila optic lobe medulla to address these questions and show that the expression of TTFs Sloppy-paired 1/2 (Slp1/2) is directly regulated at the transcriptional level by two other TTFs and the cell-cycle dependent Notch signaling through two cis-regulatory elements. We also show that supplying constitutively active Notch can rescue the delayed transition into the Slp stage in cell cycle arrested neuroblasts. Our findings reveal a novel Notch-pathway dependent mechanism through which the cell cycle progression regulates the timing of a temporal transition within a TTF transcriptional cascade.


Assuntos
Proteínas de Drosophila , Células-Tronco Neurais , Animais , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
J Biol Rhythms ; 37(5): 528-544, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35983646

RESUMO

Foraging and feeding are indispensable for survival and their timing depends not only on the metabolic state of the animal but also on the availability of food resources in their environment. Since both these aspects are subject to change over time, these behaviors exhibit rhythmicity in occurrence. As the locomotor activity of an organism is related to its disposition to acquire food, and peak feeding in fruit flies has been shown to occur at a particular time of the day, we asked if cyclic food availability can entrain their rhythmic activity. By subjecting flies to cyclic food availability, that is, feeding-starvation (FS) cycles, we provided food cues contrasting to the preferred activity times and observed if this imposed cycling in food availability could entrain the activity-rest rhythm. We found that phase control, which is a property integral to entrainment, was not achieved despite increasing starvation duration of FS cycles (FS 12:12, FS 10:14, and FS 8:16). We also found that flies subjected to T21 and T26 FS cycles were unable to match period of the activity rhythm to short or long T-cycles. Taken together, these results show that external food availability cycles do not entrain the activity-rest rhythm of fruit flies. However, we find that starvation-induced hyperactivity causes masking which results in phase changes. In addition, T-cycle experiments resulted in minor period changes during FS treatment. These findings highlight that food cyclicity by itself may not be a potent zeitgeber but may act in unison with other abiotic factors like light and temperature to help flies time their activity appropriately.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Animais , Ritmo Circadiano , Drosophila , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Temperatura
20.
Biochem Biophys Res Commun ; 626: 175-186, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-35994827

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. The pathophysiology of this disease is the formation of the Lewy body, mostly consisting of alpha-synuclein and dysfunctional mitochondria. There are two common PD-associated genes, Pink1 (encoding a mitochondrial ser/thr kinase) and Parkin (encoding cytosolic E3-ubiquitin ligase), involved in the mitochondrial quality control pathway. They assist in removing damaged mitochondria via selective autophagy (mitophagy) which if unchecked, results in the formation of protein aggregates in the cytoplasm. The role of Rab11, a small Ras-like GTPase associated with recycling endosomes, in PD is still unclear. In the present study, we used the PD model of Drosophila melanogaster and found that Rab11 has a crucial role in the regulation of mitochondrial quality control and endo-lysosomal pathways in association with Parkin and Pink1 and Rab11 acting downstream of Parkin. Additionally, overexpression of Rab11 in parkin mutant rescued the mitochondrial impairment, suggesting the therapeutic potential of Rab11 in PD pathogenesis.


Assuntos
Proteínas de Drosophila , Doença de Parkinson , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Mitofagia , Doença de Parkinson/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
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