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2.
Nat Ecol Evol ; 7(8): 1245-1256, 2023 08.
Article in English | MEDLINE | ID: mdl-37308701

ABSTRACT

While sex chromosomes carry sex-determining genes, they also often differ from autosomes in size and composition, consisting mainly of silenced heterochromatic repetitive DNA. Even though Y chromosomes show structural heteromorphism, the functional significance of such differences remains elusive. Correlative studies suggest that the amount of Y chromosome heterochromatin might be responsible for several male-specific traits, including sex-specific differences in longevity observed across a wide spectrum of species, including humans. However, experimental models to test this hypothesis have been lacking. Here we use the Drosophila melanogaster Y chromosome to investigate the relevance of sex chromosome heterochromatin in somatic organs in vivo. Using CRISPR-Cas9, we generated a library of Y chromosomes with variable levels of heterochromatin. We show that these different Y chromosomes can disrupt gene silencing in trans, on other chromosomes, by sequestering core components of the heterochromatin machinery. This effect is positively correlated to the level of Y heterochromatin. However, we also find that the ability of the Y chromosome to affect genome-wide heterochromatin does not generate physiological sex differences, including sexual dimorphism in longevity. Instead, we discovered that it is the phenotypic sex, female or male, that controls sex-specific differences in lifespan, rather than the presence of a Y chromosome. Altogether, our findings dismiss the 'toxic Y' hypothesis that postulates that the Y chromosome leads to reduced lifespan in XY individuals.


Subject(s)
Drosophila melanogaster , Sex Characteristics , Humans , Animals , Female , Male , Drosophila melanogaster/genetics , Heterochromatin/genetics , Longevity/genetics , Y Chromosome/genetics
3.
Mol Cell Endocrinol ; 533: 111339, 2021 08 01.
Article in English | MEDLINE | ID: mdl-34082046

ABSTRACT

Under conditions of nutritional and environmental stress, organismal homeostasis is preserved through inter-communication between multiple organs. To do so, higher organisms have developed a system of interorgan communication through which one tissue can affect the metabolism, activity or fate of remote organs, tissues or cells. In this review, we discuss the latest findings emphasizing Drosophila melanogaster as a powerful model organism to study these interactions and may constitute one of the best documented examples depicting the long-distance communication between organs. In flies, the adipose tissue appears to be one of the main organizing centers for the regulation of insect development and behavior: it senses nutritional and hormonal signals and in turn, orchestrates the release of appropriate adipokines. We discuss the nature and the role of recently uncovered adipokines, their regulations by external cues, their secretory routes and their modes of action to adjust developmental growth and timing accordingly. These findings have the potential for identification of candidate factors and signaling pathways that mediate conserved interorgan crosstalk.


Subject(s)
Adipokines/metabolism , Drosophila melanogaster/physiology , Fat Body/metabolism , Animals , Behavior, Animal , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Gene Expression Regulation , Homeostasis , Models, Animal
4.
Int J Mol Sci ; 21(4)2020 Feb 13.
Article in English | MEDLINE | ID: mdl-32070061

ABSTRACT

In mammals like humans, adult fitness is improved due to resource allocation, investing energy in the developmental growth process during the juvenile period, and in reproduction at the adult stage. Therefore, the attainment of their target body height/size co-occurs with the acquisition of maturation, implying a need for coordination between mechanisms that regulate organismal growth and maturation timing. Insects like Drosophila melanogaster also define their adult body size by the end of the juvenile larval period. Recent studies in the fly have shown evolutionary conservation of the regulatory pathways controlling growth and maturation, suggesting the existence of common coordinator mechanisms between them. In this review, we will present an overview of the significant advancements in the coordination mechanisms ensuring developmental robustness in Drosophila. We will include (i) the characterization of feedback mechanisms between maturation and growth hormones, (ii) the recognition of a relaxin-like peptide Dilp8 as a central processor coordinating juvenile regeneration and time of maturation, and (iii) the identification of a novel coordinator mechanism involving the AstA/KISS system.


Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Embryonic Development/genetics , Neurons/metabolism , Animals , Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Gene Expression Regulation, Developmental/genetics , Humans , Larva/genetics , Larva/growth & development , Signal Transduction/genetics
5.
Dev Cell ; 48(1): 76-86.e5, 2019 01 07.
Article in English | MEDLINE | ID: mdl-30555002

ABSTRACT

Developing organisms use fine-tuning mechanisms to adjust body growth to ever-changing nutritional conditions. In Drosophila, the secretory activity of insulin-producing cells (IPCs) is central to couple systemic growth with amino acids availability. Here, we identify a subpopulation of inhibitory neurons contacting the IPCs (IPC-connecting neurons or ICNs) that play a key role in this coupling. We show that ICNs respond to growth-blocking peptides (GBPs), a family of fat-body-derived signals produced upon availability of dietary amino acids. We demonstrate that GBPs are atypical ligands for the fly EGF receptor (EGFR). Upon activation of EGFR by adipose GBPs, ICN-mediated inhibition of IPC function is relieved, allowing insulin secretion. Our study reveals an unexpected role for EGF-like metabolic hormones and EGFR signaling as critical modulators of neural activity, coupling insulin secretion to the nutritional status.


Subject(s)
Drosophila melanogaster/metabolism , Epidermal Growth Factor/metabolism , Insulin Secretion/physiology , Insulin-Secreting Cells/metabolism , Neurons/metabolism , Animals , Drosophila Proteins/metabolism , Insulin/metabolism , Larva/metabolism , Nutritional Status/physiology
6.
Science ; 353(6307): 1553-1556, 2016 09 30.
Article in English | MEDLINE | ID: mdl-27708106

ABSTRACT

Animals adapt their growth rate and body size to available nutrients by a general modulation of insulin-insulin-like growth factor signaling. In Drosophila, dietary amino acids promote the release in the hemolymph of brain insulin-like peptides (Dilps), which in turn activate systemic organ growth. Dilp secretion by insulin-producing cells involves a relay through unknown cytokines produced by fat cells. Here, we identify Methuselah (Mth) as a secretin-incretin receptor subfamily member required in the insulin-producing cells for proper nutrient coupling. We further show, using genetic and ex vivo organ culture experiments, that the Mth ligand Stunted (Sun) is a circulating insulinotropic peptide produced by fat cells. Therefore, Sun and Mth define a new cross-organ circuitry that modulates physiological insulin levels in response to nutrients.


Subject(s)
Adipose Tissue/metabolism , Brain/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Insulin/metabolism , Membrane Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Gastrointestinal Hormone/metabolism , Animals , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Eating , Fasting/metabolism , Fat Body/metabolism , Food , Hemolymph/metabolism , Incretins/metabolism , Inhibitor of Apoptosis Proteins/metabolism , Ligands , Membrane Proteins/genetics , Organ Culture Techniques , Positive Transcriptional Elongation Factor B/metabolism , Pupa/genetics , Pupa/growth & development , Pupa/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, Gastrointestinal Hormone/genetics , TOR Serine-Threonine Kinases/metabolism
7.
Cell Metab ; 23(4): 675-84, 2016 Apr 12.
Article in English | MEDLINE | ID: mdl-27076079

ABSTRACT

Adaptation of organisms to ever-changing nutritional environments relies on sensor tissues and systemic signals. Identification of these signals would help understand the physiological crosstalk between organs contributing to growth and metabolic homeostasis. Here we show that Eiger, the Drosophila TNF-α, is a metabolic hormone that mediates nutrient response by remotely acting on insulin-producing cells (IPCs). In the condition of nutrient shortage, a metalloprotease of the TNF-α converting enzyme (TACE) family is active in fat body (adipose-like) cells, allowing the cleavage and release of adipose Eiger in the hemolymph. In the brain IPCs, Eiger activates its receptor Grindelwald, leading to JNK-dependent inhibition of insulin production. Therefore, we have identified a humoral connexion between the fat body and the brain insulin-producing cells relying on TNF-α that mediates adaptive response to nutrient deprivation.


Subject(s)
Adipokines/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/physiology , Insulin-Secreting Cells/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Body Size , Cell Line , Food Deprivation , Insulin/metabolism , Mice
8.
Curr Biol ; 23(8): R328-30, 2013 Apr 22.
Article in English | MEDLINE | ID: mdl-23618672

ABSTRACT

The Drosophila miRNA-encoding gene bantam controls cell and tissue growth. A new study now reveals that a large part of its effects on growth could come from its inhibition of the production of the molting hormone ecdysone.


Subject(s)
Drosophila melanogaster/physiology , Ecdysone/metabolism , Insulin/metabolism , MicroRNAs/metabolism , Signal Transduction , Animals
9.
Curr Biol ; 20(20): R884-6, 2010 Oct 26.
Article in English | MEDLINE | ID: mdl-20971430

ABSTRACT

DOR, a nuclear receptor co-activator conserved from flies to humans, provides a molecular connection between ecdysone and insulin signaling, two important pathways controlling developmental timing and growth, respectively.


Subject(s)
DNA-Binding Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Ecdysone/metabolism , Homeostasis/physiology , Insulin/metabolism , Signal Transduction/physiology , Animals , DNA-Binding Proteins/physiology , Drosophila Proteins/physiology , Models, Biological , Receptors, Steroid/metabolism
10.
Dev Cell ; 18(6): 1012-21, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20627082

ABSTRACT

How steroid hormones shape animal growth remains poorly understood. In Drosophila, the main steroid hormone, ecdysone, limits systemic growth during juvenile development. Here we show that ecdysone controls animal growth rate by specifically acting on the fat body, an organ that retains endocrine and storage functions of the vertebrate liver and fat. We demonstrate that fat body-targeted loss of function of the Ecdysone receptor (EcR) increases dMyc expression and its cellular functions such as ribosome biogenesis. Moreover, changing dMyc levels in this tissue is sufficient to affect animal growth rate. Finally, the growth increase induced by silencing EcR in the fat body is suppressed by cosilencing dMyc. In conclusion, the present work reveals an unexpected function of dMyc in the systemic control of growth in response to steroid hormone signaling.


Subject(s)
Adipocytes/metabolism , DNA-Binding Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila/growth & development , Ecdysone/metabolism , Fat Body/growth & development , Juvenile Hormones/metabolism , Larva/growth & development , Transcription Factors/metabolism , Adipocytes/cytology , Animals , Cell Differentiation/physiology , Cell Enlargement , DNA-Binding Proteins/genetics , Drosophila/cytology , Drosophila Proteins/genetics , Fat Body/cytology , Gene Silencing/physiology , Growth Inhibitors/genetics , Growth Inhibitors/metabolism , Larva/cytology , Protein Biosynthesis/physiology , Receptors, Steroid/genetics , Ribosomes/genetics , Ribosomes/metabolism , Signal Transduction/physiology , Transcription Factors/genetics , Up-Regulation/physiology
11.
Dev Cell ; 17(6): 874-84, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20059956

ABSTRACT

In metazoans, tissue growth relies on the availability of nutrients--stored internally or obtained from the environment--and the resulting activation of insulin/IGF signaling (IIS). In Drosophila, growth is mediated by seven Drosophila insulin-like peptides (Dilps), acting through a canonical IIS pathway. During the larval period, animals feed and Dilps produced by the brain couple nutrient uptake with systemic growth. We show here that, during metamorphosis, when feeding stops, a specific DILP (Dilp6) is produced by the fat body and relays the growth signal. Expression of DILP6 during pupal development is controlled by the steroid hormone ecdysone. Remarkably, DILP6 expression is also induced upon starvation, and both its developmental and environmental expression require the Drosophila FoxO transcription factor. This study reveals a specific class of ILPs induced upon metabolic stress that promotes growth in conditions of nutritional deprivation or following developmentally induced cessation of feeding.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Drosophila melanogaster/metabolism , Somatomedins/metabolism , Animals , Drosophila Proteins/genetics , Ecdysone/metabolism , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Developmental , Signal Transduction , Somatomedins/genetics , Starvation/metabolism
12.
Dev Cell ; 13(4): 523-38, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17925228

ABSTRACT

In Drosophila oocytes, dorso-anterior transport of gurken mRNA requires both the Dynein motor and the heterogeneous nuclear ribonucleoprotein (hnRNP) Squid. We show that gurken transcripts are transported directly on microtubules by Dynein in nonmembranous electron-dense transport particles that also contain Squid and the transport cofactors Egalitarian and Bicaudal-D. At its destination, gurken mRNA is statically anchored by Dynein within large electron-dense cytoplasmic structures known as sponge bodies. Egalitarian and Bicaudal-D contribute only to active transport, whereas Dynein and Squid are also required for gurken mRNA anchoring and the integrity of sponge bodies. Disrupting Dynein function disperses gurken mRNA homogeneously throughout the cytoplasm, whereas the loss of Squid function converts the sponge bodies into active transport particles. We propose that Dynein acts as a static structural component for the assembly of gurken mRNA transport and anchoring complexes, and that Squid is required for the dynamic conversion of transport particles to sponge bodies.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Dyneins/physiology , Heterogeneous-Nuclear Ribonucleoproteins/physiology , RNA, Messenger/metabolism , Transforming Growth Factor alpha/metabolism , Animals , Biological Transport, Active , Cytoplasm/metabolism , Cytoplasm/ultrastructure , Drosophila Proteins/genetics , Drosophila Proteins/physiology , Microtubules/metabolism , Microtubules/ultrastructure , RNA Transport , Transforming Growth Factor alpha/genetics
13.
Genes Cells ; 11(8): 907-18, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16866874

ABSTRACT

In Drosophila, the Vestigial-Scalloped (VG-SD) dimeric transcription factor is required for wing cell identity and proliferation. Previous results have shown that VG-SD controls expression of the cell cycle positive regulator dE2F1 during wing development. Since wing disc growth is a homeostatic process, we investigated the possibility that genes involved in cell cycle progression regulate vg and sd expression in feedback loops. We focused our experiments on two major regulators of cell cycle progression: dE2F1 and the antagonist dacapo (dap). Our results reinforce the idea that VG/SD stoichiometry is critical for correct development and that an excess in SD over VG disrupts wing growth. We reveal that transcriptional activity of VG-SD and the VG/SD ratio are both modulated by down-expression of cell cycle genes. We also detected a dap-induced sd up-regulation that disrupts wing growth. Moreover, we observed a rescue of a vg hypomorphic mutant phenotype by dE2F1 that is concomitant with vg and sd induction. This regulation of the VG-SD activity by dE2F1 is dependent on the vg genetic background. Our results support the hypothesis that cell cycle genes fine-tune wing growth and cell proliferation, in part, through control of the VG/SD stoichiometry and activity. This points to a homeostatic feedback regulation between proliferation regulators and the VG-SD wing selector.


Subject(s)
Cell Proliferation , Drosophila Proteins/metabolism , Drosophila/embryology , Genes, cdc/physiology , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Wings, Animal/embryology , Animals , E2F1 Transcription Factor/metabolism , Feedback, Physiological , Gene Expression Regulation , Homeostasis/genetics , Mutant Proteins/metabolism , Transcriptional Activation , Transfection , Wings, Animal/growth & development
14.
Cell Cycle ; 5(7): 740-9, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16582629

ABSTRACT

In vitro studies have shown that Drosophila melanogaster has a highly efficient single deoxyribonucleoside kinase (dNK) multisubstrate enzyme. dNK is related to the mammalian Thymidine Kinase 2 (TK2) group involved in the nucleotide synthesis salvage pathway. To study the dNK function in vivo, we constructed transgenic Drosophila strains and impaired the nucleotide de novo synthesis pathway, using antifolates such as aminopterin. Our results show that dNK overexpression rescues both cell death and cell cycle arrest triggered by this anti-cancer drug, and confers global resistance on the fly. Moreover, we show that fly viability and growth depend on the exquisite ratio between dNK expression and its substrate thymidine (dT) in the medium, and that increased dT concentrations trigger apoptosis and a decrease in body mass when dNK is mis-expressed. Finally, dNK expression, unlike that of TK2, is cell cycle dependent and under the control of CyclinE and the dE2F1 transcription factor involved in the G1/S transition. dNK is therefore functionally more closely related to mammalian TK1 than to TK2. This strongly suggests that dNK plays a role in cell proliferation in physiological conditions.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle/physiology , Drosophila melanogaster/cytology , Drosophila melanogaster/enzymology , Drug Resistance, Neoplasm , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Aminopterin/pharmacology , Animals , Cell Proliferation , Cell Survival , Drosophila melanogaster/drug effects , E2F1 Transcription Factor/metabolism , Gene Expression Regulation , Methotrexate/pharmacology , Phenotype , Thymidine/metabolism
15.
Cell ; 122(1): 97-106, 2005 Jul 15.
Article in English | MEDLINE | ID: mdl-16009136

ABSTRACT

Molecular motors actively transport many types of cargo along the cytoskeleton in a wide range of organisms. One class of cargo is localized mRNAs, which are transported by myosin on actin filaments or by kinesin and dynein on microtubules. How the cargo is kept at its final intracellular destination and whether the motors are recycled after completion of transport are poorly understood. Here, we use a new RNA anchoring assay in living Drosophila blastoderm embryos to show that apical anchoring of mRNA after completion of dynein transport does not depend on actin or on continuous active transport by the motor. Instead, apical anchoring of RNA requires microtubules and involves dynein as a static anchor that remains with the cargo at its final destination. We propose a general principle that could also apply to other dynein cargo and to some other molecular motors, whereby cargo transport and anchoring reside in the same molecule.


Subject(s)
Biological Transport/physiology , Blastoderm/physiology , Drosophila/embryology , Drosophila/physiology , Dyneins/physiology , RNA, Messenger/metabolism , Animals , Blastoderm/ultrastructure , Cytoplasm/physiology , Cytoplasm/ultrastructure , Drosophila/ultrastructure , Dyneins/metabolism , Microtubules/physiology , Microtubules/ultrastructure
16.
Genes Cells ; 7(12): 1255-66, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12485165

ABSTRACT

BACKGROUND: Compartment formation is a developmental process that requires the existence of barriers against intermixing between cell groups. In the Drosophila wing disc, the dorso-ventral (D/V) compartment boundary is defined by the expression of the apterous (ap) selector gene in the dorsal compartment. AP activity is under control of dLMO which destabilizes the formation of the AP-CHIP complex. RESULTS: We report that D/V boundary formation in the wing disc also depends on early expression of vestigial (vg). Our data suggest that vg is already required for wing cell proliferation before D/V compartmentalization. In addition, we show that over-expression of vg can, to some extent, rescue the effect of the absence of ap on D/V boundary formation. Early VG product regulates AP activity by inducing dLMO and thus indirectly regulating ap target genes such as fringe and the PSalpha1 and PSalpha2 integrins. CONCLUSION: Normal cell proliferation is necessary for ap expression at the level of the D/V boundary. This would be mediated by vg, which interacts in a dose-dependent way with ap.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Gene Expression Regulation, Developmental , Homeodomain Proteins/metabolism , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Animals , Cell Division/physiology , Drosophila Proteins/genetics , Drosophila melanogaster/anatomy & histology , Drosophila melanogaster/genetics , Integrin alpha Chains , Integrins/genetics , Integrins/metabolism , LIM-Homeodomain Proteins , Morphogenesis , N-Acetylglucosaminyltransferases/genetics , N-Acetylglucosaminyltransferases/metabolism , Nuclear Proteins/genetics , Phenotype , Wings, Animal/cytology , Wings, Animal/growth & development , Wings, Animal/physiology
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