| 1. |
- Goergen, Philip, et al.
(författare)
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The Drosophila Small GTPase Rac2 is Required for Normal Feeding and Mating Behaviour.
- 2014
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Ingår i: Behavior Genetics. - : Springer Science and Business Media LLC. - 0001-8244 .- 1573-3297. ; 44:2, s. 155-64
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Tidskriftsartikel (refereegranskat)abstract
- All multicellular organisms require the ability to regulate bodily processes in order to maintain a stable condition, which necessitates fluctuations in internal metabolics, as well as modifications of outward behaviour. Understanding the genetics behind this modulation is important as a general model for the metabolic modification of behaviour. This study demonstrates that the activity of the small GTPase Rac2 is required in Drosophila for the proper regulation of lipid storage and feeding behaviour, as well as aggression and mating behaviours. Rac2 mutant males and females are susceptible to starvation and contain considerably less lipids than controls. Furthermore, Rac2 mutants also have disrupted feeding behaviour, eating fewer but larger meals than controls. Intriguingly, Rac2 mutant males rarely initiate aggressive behaviour and display significantly increased levels of courtship behaviour towards other males and mated females. From these results we conclude that Rac2 has a central role in regulating the Drosophila homeostatic system.
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| 2. |
- Goergen, Philip, 1986-
(författare)
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The Molecular Mechanism of Aggression and Feeding Behaviour in Drosophila melanogaster
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is a complex disorder which has become a growing health concern. Twin studies have demonstrated a strong genetic component to the development of obesity and genome wide association studies have identified several genetic loci associated with it. However, most of these loci are still poorly understood in a functional context. Interestingly, many of the hormones and neurobiological messengers responsible for regulating feeding behaviour and metabolism are also linked to controlling aggression, but it is still not understood how they interact to maintain metabolic homeostasis. In this thesis, the model organism Drosophila melanogaster was employed to dissect the molecular mechanisms of the genetic cascades regulating aggressive behaviour and metabolic homeostasis.In paper I and II, the role of transcription factor AP-2 (TfAP-2) and Tiwaz Twz, Drosophila homologues of two human obesity-linked genes were investigated in aggression and feeding behaviour. Paper I demonstrated that TfAP-2 and Twz genetically interact in octopaminergic neurons to modulate male aggression by controlling the expression of genes necessary for octopamine (fly analogue of noradrenaline) production and secretion. Moreover, it was revealed that octopamine in turn regulates aggression through the Drosophila cholecystokinin (CCK) satiation hormone homologue Drosulfakinin (Dsk). Paper II revealed that TfAP-2 and Twz also initiate feeding through regulation of octopamine poduction and secretion. Octopamine then induces Dsk expression leading to inhibition of feeding.Paper III established that the activity of the small GTPase Ras-related C3 botulinum toxin substrate 2 (Rac2) is required in Drosophila for the proper regulation of metabolic homeostasis, as well as overt behaviours. Rac2 mutants were starvation susceptible, had less lipids and exhibited disrupted feeding behaviour. Moreover, they displayed aberrant aggression and courtship behaviour towards conspecifics.Paper IV studied Protein kinase D (PKD), the homologue of a third obesity-linked gene PRKD1, and another kinase Stretchin-Mlck (Strn-Mlck). Reducing PKD transcript levels in the insulin producing cells led to flies with increased starvation susceptibility, decreased levels of lipids and diminished insulin signalling compared to controls. Reduced Strn-Mlck expression resulted in a starvation phenotype and slight reduction in insulin signalling and lipid content. These findings imply a function for PKD and Strn-Mlck in insulin release.
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| 3. |
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| 4. |
- Luo, Jiangnan, et al.
(författare)
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Drosophila Insulin-Producing Cells Are Differentially Modulated by Serotonin and Octopamine Receptors and Affect Social Behavior
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e99732-
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Tidskriftsartikel (refereegranskat)abstract
- A set of 14 insulin-producing cells (IPCs) in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5). Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.
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| 5. |
- Williams, Michael J, et al.
(författare)
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Regulation of aggression by obesity-linked genes TfAP-2 and Twz through octopamine signaling in Drosophila
- 2014
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 196:1, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- In Drosophila, the monoamine octopamine, through mechanisms that are not completely understood, regulates both aggression and mating behavior. Interestingly, our study demonstrates that the Drosophila obesity-linked homologs Transcription factor AP-2 (TfAP-2; TFAP2B in humans) and Tiwaz (Twz; KCTD15 in humans) interact to modify male behavior by controlling the expression of Tyramine β-hydroxylase and Vesicular monanime transporter, genes necessary for octopamine production and secretion. Furthermore, we reveal that octopamine in turn regulates aggression through the Drosophila cholecystokinin satiation hormone homolog Drosulfakinin (Dsk). Finally, we establish that TfAP-2 is expressed in octopaminergic neurons known to control aggressive behavior and that TfAP-2 requires functional Twz for its activity. We conclude that genetically manipulating the obesity-linked homologs TfAP-2 and Twz is sufficient to affect octopamine signaling, which in turn modulates Drosophila male behavior through the regulation of the satiation hormone Dsk.
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| 6. |
- Williams, Michael J., et al.
(författare)
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The Drosophila Kctd-family homologue Kctd12-like modulates male aggression and mating behaviour
- 2014
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 40:3, s. 2513-2526
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Tidskriftsartikel (refereegranskat)abstract
- In Drosophila, serotonin (5-HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12-family of proteins, which have been shown to modify G-protein-coupled receptor (GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5-HT receptor signalling. The KCTD12-family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12-like (Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5-HT receptor 5-HT7, and we observed that both Ktl and the 5-HT1A receptor are required in insulin-producing cells (IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5-HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin-hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5-HT1A receptor. Similar to what was observed with mammalian KCTD12-family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5-HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour.
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| 7. |
- Williams, Michael, et al.
(författare)
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Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster
- 2014
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:9, s. e1004499-
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Tidskriftsartikel (refereegranskat)abstract
- In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.
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