A Drosophila RNAi collection is subject to dominant phenotypic effects

Green, Edward W.; Fedele, Giorgio; Giorgini, Flaviano; Kyriacou, Charalambos P.

doi:10.1038/nmeth.2856

Cited by 100 publications

(137 citation statements)

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“…These deviations could be caused either by own effect of UAS-RNAi transgenes or by difference in genetic background between the host strains and RNAi lines. Recently Green et al 37 reported that transgenic RNAi-inducing lines from the VDRC libraries are subject to dominant phenotypic effects. Specifically, on crossing 39 randomly selected KK lines to the panneuronal driver elav-GAL4c155, 9 of them produced F1 progeny unable to properly inflate their wings.…”

Section: Discussionmentioning

confidence: 99%

The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production inDrosophila melanogaster

Fedotov

Bragina

Besedina

et al. 2014

Fly

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A Panova & Nikolai G Kamyshev (2014) The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production in Drosophila melanogaster, Fly, 8:3, 176-187, DOI: 10.4161/19336934.2014.983389 To link to this article: https://doi.org/10. 4161/19336934.2014.983389 Molecular mechanisms underlying the functioning of central pattern generators (CPGs) are poorly understood. Investigations using genetic approaches in the model organism Drosophila may help to identify unknown molecular players participating in the formation or control of motor patterns. Here we report Drosophila genes as candidates for involvement in the neural mechanisms responsible for motor functions, such as locomotion and courtship song. Twenty-two Drosophila lines, used for gene identification, were isolated from a previously created collection of 1064 lines, each carrying a P element insertion in one of the autosomes. The lines displayed extreme deviations in locomotor and/or courtship song parameters compared with the whole collection. The behavioral consequences of CNS-specific RNAi-mediated knockdowns for 10 identified genes were estimated. The most prominent changes in the courtship song interpulse interval (IPI) were seen in flies with Sps2 or CG15630 knockdown. Glia-specific knockdown of these genes produced no effect on the IPI. Estrogen-induced knockdown of CG15630 in adults reduced the IPI. The product of the CNS-specific gene, CG15630 (a predicted cell surface receptor), is likely to be directly involved in the functioning of the CPG generating the pulse song pattern. Future studies should ascertain its functional role in the neurons that constitute the song CPG. Other genes (Sps2, CG34460), whose CNS-specific knockdown resulted in IPI reduction, are also worthy of detailed examination.

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Section: Discussionmentioning

confidence: 99%

The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production inDrosophila melanogaster

Fedotov

Bragina

Besedina

et al. 2014

Fly

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“…cn and v RNAi lines are part of the phiC31 RNAi Library (KK) and were obtained from the Vienna Drosophila RNAi Center (53). The gene encoding kynurenine aminotransferase (hKAT) was amplified from a human fetal cDNA library (54) and cloned into the pJFRC2 vector (55)-a gift from Gerald Rubin (Addgene plasmid no.…”

Section: Methodsmentioning

confidence: 99%

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Breda

Sathyasaikumar

Idrissi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.T he kynurenine pathway (KP), the major catabolic route of tryptophan (TRP) metabolism in mammals ( Fig. 1), has been closely linked to the pathogenesis of several brain disorders (1). This pathway contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA) (2). QUIN is a well-characterized endogenous neurotoxin that specifically activates N-methyl-D-aspartate (NMDA) receptors, thereby inducing excitotoxicity (3, 4). The metabolites 3-HK and QUIN are also neurotoxic via the generation of free radicals and oxidative stress (5, 6). Conversely, KYNA-synthesized by kynurenine aminotransferases (KATs)-is neuroprotective through its antioxidant properties and antagonism of both the α7 nicotinic acetylcholine receptor and the glycine coagonist site of the NMDA receptor (7-13). Levels of these metabolites are regulated at two critical points in the KP: (i) the initial, rate-limiting conversion of TRP into N-formylkynurenine by either tryptophan-2,3-dioxygenase (TDO) or indoleamine-2,3-dioxygenase 1 and 2 (IDO1 and IDO2); and (ii) synthesis of 3-HK from kynurenine by the flavoprotein kynurenine-3-monoxygenase (KMO) (1).Alterations in levels of the KP metabolites have been observed in a broad range of brain disorders, including both neurodegenerative and psychiatric conditions (14). In neurodegenerative diseases such as Huntington's (HD), Parkinson's (PD), and Alzheimer's...

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“…A recent letter to the editor included data showing that the KK RNAi library used in this study has a nonannotated docking site into which most RNAi integrations occurred (Green et al 2014). All lines tested in that study (39) had RNAi insertion elements in the nonannotated site.…”

Section: Fly Husbandrymentioning

confidence: 99%

“…Using PCR primers designed by Green et al (2014), we assayed seven lines along with the control line, 60100. The control line had neither site filled, as expected.…”

Section: Fly Husbandrymentioning

confidence: 99%

Identification of Genes That Promote or Inhibit Olfactory Memory Formation in Drosophila

et al. 2015

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Genetic screens in Drosophila melanogaster and other organisms have been pursued to filter the genome for genetic functions important for memory formation. Such screens have employed primarily chemical or transposon-mediated mutagenesis and have identified numerous mutants including classical memory mutants, dunce and rutabaga. Here, we report the results of a large screen using panneuronal RNAi expression to identify additional genes critical for memory formation. We identified .500 genes that compromise memory when inhibited (low hits), either by disrupting the development and normal function of the adult animal or by participating in the neurophysiological mechanisms underlying memory formation. We also identified .40 genes that enhance memory when inhibited (high hits). The dunce gene was identified as one of the low hits and further experiments were performed to map the effects of the dunce RNAi to the a/b and g mushroom body neurons. Additional behavioral experiments suggest that dunce knockdown in the mushroom body neurons impairs memory without significantly affecting acquisition. We also characterized one high hit, sickie, to show that RNAi knockdown of this gene enhances memory through effects in dopaminergic neurons without apparent effects on acquisition. These studies further our understanding of two genes involved in memory formation, provide a valuable list of genes that impair memory that may be important for understanding the neurophysiology of memory or neurodevelopmental disorders, and offer a new resource of memory suppressor genes that will aid in understanding restraint mechanisms employed by the brain to optimize resources.

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A Drosophila RNAi collection is subject to dominant phenotypic effects

Cited by 100 publications

References 3 publications

The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production inDrosophila melanogaster

The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production inDrosophila melanogaster

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Identification of Genes That Promote or Inhibit Olfactory Memory Formation in Drosophila

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