title: Combination of hypomorphic mutations of the Drosophila homologues of aryl hydrocarbon receptor and nucleosome assembly protein family genes disrupts morphogenesis, memory and detoxification.
abstract: Aryl hydrocarbon receptor is essential for biological responses to endogenous and exogenous toxins in mammals. Its Drosophila homolog spineless plays an important role in fly morphogenesis. We have previously shown that during morphogenesis spineless genetically interacts with CG5017 gene, which encodes a nucleosome assembly factor and may affect cognitive function of the fly. We now demonstrate synergistic interactions of spineless and CG5017 in pathways controlling oxidative stress response and long-term memory formation in Drosophila melanogaster. Oxidative stress was induced by low doses of X-ray irradiation of flies carrying hypomorphic mutation of spineless, mutation of CG5017, and their combination. To determine the sensitivity of these mutants to pharmacological modifiers of the irradiation effect, we irradiated flies growing on standard medium supplemented by radiosensitizer furazidin and radioprotector serotonin. The effects of irradiation were investigated by analyzing leg and antenna morphological structures and by using real-time PCR to measure mRNA expression levels for spineless, Cyp6g1 and Gst-theta genes. We also examined long-term memory in these mutants using conditioned courtship suppression paradigm. Our results show that the interaction of spineless and CG5017 is important for regulation of morphogenesis, long-term memory formation, and detoxification during oxidative stress. Since spineless and CG5017 are evolutionary conserved, these results must be considered when evaluating the risk of combining similar mutations in other organisms, including humans.
authors.affiliation: Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; NBIC, Moscow Institute of Physics and Technology, Moscow, Russia.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Kuzin
authors.affiliation: Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Nikitina
authors.affiliation: Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Roman O
authors.initials: RO
authors.lastname: Cherezov
authors.affiliation: Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Vorontsova
authors.affiliation: Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Slezinger
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; NBIC, Moscow Institute of Physics and Technology, Moscow, Russia.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Zatsepina
authors.affiliation: Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Simonova
authors.affiliation: NBIC, Moscow Institute of Physics and Technology, Moscow, Russia; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
authors.forename: Grigori N
authors.initials: GN
authors.lastname: Enikolopov
authors.affiliation: Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Savvateeva-Popova
mesh_terms: D000818:Animals; D004330:Drosophila / Q000196:embryology / Q000235:genetics* / Q000378:metabolism* / Q000528:radiation effects; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000528:radiation effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000235:genetics; D007858:Learning; D008297:Male; D008568:Memory; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D009707:Nucleosomes; D010641:Phenotype; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D014965:X-Rays
chemical_list: D029721:Drosophila Proteins; D009687:Nuclear Proteins; D009707:Nucleosomes; D018336:Receptors, Aryl Hydrocarbon; C581218:mil protein, Drosophila; C112211:ss protein, Drosophila; D012701:Serotonin; D005982:Glutathione Transferase
references.citation: Chem Biol Interact. 2002 Sep 20;141(1-2):131-60
references.pmid: 12213389
references.citation: J Invest Dermatol. 2011 Jan;131(1):203-10
references.pmid: 20861855
references.citation: Nucleic Acids Res. 2002 May 1;30(9):e36
references.pmid: 11972351
references.citation: Curr Biol. 2003 Feb 18;13(4):286-96
references.pmid: 12593794
references.citation: FEBS Lett. 2013 Apr 2;587(7):922-9
references.pmid: 23454210
references.citation: Curr Drug Metab. 2012 Jul;13(6):787-814
references.pmid: 22571481
references.citation: J Biol Chem. 1995 Nov 3;270(44):26292-302
references.pmid: 7592839
references.citation: PLoS One. 2010 Nov 08;5(11):e15382
references.pmid: 21079739
references.citation: Genes Dev. 1998 May 1;12(9):1290-303
references.pmid: 9573046
references.citation: Development. 1999 Sep;126(17):3937-45
references.pmid: 10433921
references.citation: Environ Health Perspect. 2009 Jul;117(7):1139-46
references.pmid: 19654925
references.citation: BMC Neurosci. 2002 Jul 30;3:9
references.pmid: 12149133
references.citation: Radiobiologiia. 1984 Mar-Apr;24(2):236-40
references.pmid: 6729069
references.citation: J Cardiovasc Dis Res. 2011 Apr;2(2):91-5
references.pmid: 21814412
references.citation: Int J Radiat Biol. 1994 Jan;65(1):27-33
references.pmid: 7905906
references.citation: Gene. 2001 Oct 31;278(1-2):223-34
references.pmid: 11707340
references.citation: Genomics. 1997 Sep 15;44(3):253-65
references.pmid: 9325046
references.citation: J Mol Model. 2012 May;18(5):1755-66
references.pmid: 21833825
references.citation: Learn Mem. 1999 Jan-Feb;6(1):1-20
references.pmid: 10355520
references.citation: J Exp Zool A Comp Exp Biol. 2006 Sep 1;305(9):693-706
references.pmid: 16902966
references.citation: J Biol Chem. 2010 Aug 6;285(32):24388-97
references.pmid: 20511231
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1248-53
references.pmid: 16432217
references.citation: J Neural Transm (Vienna). 2000;107(5):581-601
references.pmid: 11072753
references.citation: Dev Biol. 2004 Jun 1;270(1):64-75
references.pmid: 15136141
references.citation: Behav Genet. 2001 Jan;31(1):17-27
references.pmid: 11529271
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2844-9
references.pmid: 9501178
references.citation: Ontogenez. 2010 Sep-Oct;41(5):364-9
references.pmid: 21061663
references.citation: Ontogenez. 1991 Mar-Apr;22(2):212-6
references.pmid: 1677464
references.citation: Ukr Biokhim Zh (1999). 2008 Jul-Aug;80(4):59-65
references.pmid: 19140451
references.citation: Nature. 1972 Jun 16;237(5355):402-3
references.pmid: 4557327
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20768-73
references.pmid: 21068375
references.citation: Proc Natl Acad Sci U S A. 1979 Jul;76(7):3430-4
references.pmid: 16592682