ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila

Voet, Monique van der; Harich, Benjamin; Franke, Barbara; Schenck, Annette

doi:10.1038/mp.2015.55

Cited by 87 publications

(95 citation statements)

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“…As the important components of GPCRs, LPHs can pass exogenous spider toxin a-LTX signal thereby affecting their growth, development, adaptability, and schizophrenia and other diseases occur in vertebrates (Jeon et al, 2016;O'Hayre et al, 2013;Sumbayev et al, 2016;Van Der Voet et al, 2015). However, the functions and signal transduction pathways of LPH in most insects are still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…While, lph-3 null mutant mice displayed a hyperactive phenotype accompanied by increasing dopamine and serotonin in the dorsal striatal, which were also sensitive to the locomotor after stimulation by cocaine (psychostimulants; Wallis et al, 2012). Knockdown of CG8639/lph induced hyperactivity and loss sleep in a pattern resembling dopamine transporter knockdown in Drosophila melanogaster (Van Der Voet, Harich, Franke, & Schenck, 2015). Such corroborating phenotypes for lph-3 genetic defects unveil a possible overlap between the function of lph-3 and molecular components of monoamine signal pathway such as dopamine and serotonin receptors or transporters.…”

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confidence: 99%

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Identification and evolution of latrophilin receptor gene involved in Tribolium castaneum devolopment and female fecundity

Gao

Liu

et al. 2017

Genesis

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Latrophilins (LPHs) are adhesion G-protein-coupled receptors comprising three paralogous forms (LPH-1, LPH-2, and LPH-3) and known receptors for α-latrotoxin, which are involved in growth, development, adaptability, and schizophrenia and other diseases in vertebrates. However, the functions of LPH are poorly understood in most insects. Here, phylogenetic and synteny analysis indicated that LPH-1 and LPH-3 evolved separately from a common ancestor LPH-2. Then, latrophilin (Tclph) was cloned in Tribolium castaneum, and three alternatively spliced transcripts (Tclpha, Tclphb and Tclphc) were identified. All these three Tclphs were highest expressed at the early adult stage, and strongly expressed in central nervous system of adults. Larval RNA interference (RNAi) against Tclph caused 24% adult wing abnormal, 30% insect death, and led to 100% reductions in beetle fecundity. Fecundity deficiency was rescued by reciprocal crosses with wild-type females, but not males. And dissection results revealed that 63% of dsTclph female ovaries were atrophied. Further, exon-specific RNAi illustrated that neither knockdown of Tclpha nor Tclphc resulted in development defects and reductions in beetle fecundity. Thus, it indicated that Tclphb was essential for development and female fecundity in T. castaneum. Moreover, Tclph knockdown increased the expression of the foxo, plc, and pka genes, which most likely modulated the effects of Tclph on development and reproduction in T. castaneum.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Identification and evolution of latrophilin receptor gene involved in Tribolium castaneum devolopment and female fecundity

Gao

Liu

et al. 2017

Genesis

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“…available on FlyBase(GRAMATES et al 2017) to determine if altered activity phenotypes399 have been described associated with the candidate genes identified here. Mutants in 400 25 of the candidate genes have been described as either "flightless", or "flight defective" 401 on FlyBase (GRAMATES et al 2017), five were described as "uncoordinated," and one 402 (Cirl) was described as "hyperactive" and "sleep defective" (VAN DERVOET et al 2015).403Based on their molecular functions and previously described phenotypes, 10 genes404 were selected for follow-up and mutant/RNAi lines were obtained: eIF5B (eukaryotic 405 translation initiation factor 5B; LASKO 2000; JOHNSTONE AND LASKO 2004), Su(z)2 (a 406 member of the Polycomb Repressive Complex 1 [PRC1]; WU AND HOWE 1995; LO et al 407 2009; NGUYEN et al 2017), wde (a cofactor of the H3K9 histone methyltransferase 408 EGG; KOCH et al 2009; YU et al 2015), Cirl (a Calcium-independent receptor for α-409 latrotoxin with hyperactivity phenotype; ANDERSEN et al 2015; SCHOLZ et al 2015; 410 21 SCHOLZ et al 2017), nwk (an SH3 adaptor protein regulating synaptic growth; COYLE et 411 al. 2004b; O'CONNOR-GILES et al 2008; RODAL et al 2008a), SmydA-9 (an arthropod-412 specific SET and MYND domain; THOMPSON AND TRAVERS 2008), cpo (controls various 413 neurological functions; BELLEN et al 1992a; BELLEN et al 1992b) (GLASSCOCK AND 414 TANOUYE 2005), Prosap (also an SH3 domain containing proteins involved in neuronal 415 development; DIAGANA et al 2002; HARRIS et al 2016; WU et al 2017), jus (a gene with 416 links to seizures; ZHANG et al 2002; MARLEY AND BAINES 2011; DEAN et al 2018), and 417 Jarid2 (a Jumonji C domain-containing lysine demethylase; SASAI et al 2007; HERZ et al 418 2012).…”

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confidence: 99%

Genetic networks underlying natural variation in basal and induced activity levels inDrosophila melanogaster

Watanabe

Gordon

Riddle

2018

Preprint

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Exercise is recommended by health professionals across the globe as part of a healthy lifestyle to prevent and/or treat the consequences of obesity. While overall, the health benefits of exercise and an active lifestyle are well understood, very little is known about how genetics impacts an individual’s inclination for and response to exercise. To address this knowledge gap, we investigated the genetic architecture underlying natural variation in activity levels in the model system Drosophila melanogaster. Activity levels were assayed in the Drosophila Genetics Reference Panel 2 fly strains at baseline and in response to a gentle exercise treatment using the Rotational Exercise Quantification System. We found significant, sex-dependent variation in both activity measures and identified over 100 genes that contribute to basal and induced exercise activity levels. This gene set was enriched for genes with functions in the central nervous system and in neuromuscular junctions and included several candidate genes with known activity phenotypes such as flightlessness or uncoordinated movement. Interestingly, there were also several chromatin proteins among the candidate genes, two of which were validated and shown to impact activity levels. Thus, the study described here reveals the complex genetic architecture controlling basal and exercise-induced activity levels in D. melanogaster and provides a resource for exercise biologists.

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“…We have recently demonstrated increased locomoter activity and decreased sleep in ADHD Drosophila models [van der Voet et al, ]. We therefore assessed whether Git pan‐neuronal knockdown flies also affect locomotor behavior.…”

Section: Resultsmentioning

confidence: 99%

Converging evidence does not support GIT1 as an ADHD risk gene

Klein

Voet

Harich

et al. 2015

American J of Med Genetics Pt B

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Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N ¼ 19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N ¼ 225), and (3) the Brain Imaging Genetics cohort (BIG, N ¼ 1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene 492Neuropsychiatric Genetics expression do not appear to have ADHD-related behavioral consequences. Ó 2015 Wiley Periodicals, Inc.Key words: GIT1; ADHD; brain imaging genetics; eQTL; Drosophila melanogaster INTRODUCTIONAttention Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder (heritability 70-80% [Faraone et al., 2005;Burt 2009]), with prevalence rates of 5-6% in childhood [Polanczyk et al., 2007; American Psychiatric Association 2013]. Clinically, ADHD is characterized by two core symptom domains: inattention and hyperactivity/impulsivity [American Psychiatric Association, 2013]. At least 15% and up to 60% of all patients diagnosed in childhood still meet full ADHD criteria when they reach adulthood; prevalence rates of persistent ADHD in adults range between 2.5 and 4.9% [Simon et al., 2009]. The clinical manifestation of adult ADHD may differ from that of childhood ADHD, i.e., by less obvious symptoms of hyperactivity and impulsivity [Haavik et al., 2010;. However, adult individuals with ADHD might be the most severe cases, given the lifelong impairment [Franke et al., 2012 ;Dalsgaard et al., 2015].Despite its high heritability, identifying ADHD risk genes has been difficult [Franke et al., 2009a;Gizer et al., 2009], Due to the disorder's complex genetic background [Franke et al., 2012]. Because of the high prevalence of ADHD in the population, the search for...

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ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila

Cited by 87 publications

References 81 publications

Identification and evolution of latrophilin receptor gene involved in Tribolium castaneum devolopment and female fecundity

Identification and evolution of latrophilin receptor gene involved in Tribolium castaneum devolopment and female fecundity

Genetic networks underlying natural variation in basal and induced activity levels inDrosophila melanogaster

Converging evidence does not support GIT1 as an ADHD risk gene

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