Mechanisms Underlying Hypoxia Tolerance in Drosophila melanogaster hairy as a Metabolic Switch 英文参考文献.docVIP

MechanismsUnderlyingHypoxiaToleranceinDrosophila melanogaster:hairyasaMetabolicSwitch DanZhou1,2*,JinXue1,2,JamesC.K.Lai3,NicholasJ.Schork4,KevinP.White5,6,GabrielG.Haddad1,2 * 1DepartmentsofPediatrics(SectionofRespiratoryMedicine)andNeuroscience,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,2Rady Children’sHospital–SanDiego,SanDiego,California,UnitedStatesofAmerica,3CollegeofPharmacy,IdahoStateUniversity,Pocatello,Idaho,UnitedStatesofAmerica, 4DepartmentofMolecularandExperimentalMedicine,TheScrippsResearchInstitute,LaJolla,California,UnitedStatesofAmerica,5InstituteforGenomicsandSystems Biology,TheUniversityofChicago,Chicago,Illinois,UnitedStatesofAmerica,6DepartmentsofHumanGeneticsandEcologyandEvolution,TheUniversityofChicago, Chicago,Illinois,UnitedStatesofAmerica Abstract Hypoxia-inducedcellinjuryhasbeenrelatedtomultiplepathologicalconditions.Inordertorenderhypoxia-sensitivecells andtissuesresistanttolowO2environment,inthiscurrentstudy,weusedDrosophilamelanogasterasamodeltodissect themechanismsunderlyinghypoxia-tolerance.AD.melanogasterstrainthatlivesperpetuallyinanextremelylow-oxygen environment (4% O2, an oxygen level that is equivalent to that over about 4,000m above Mt. Everest) was generated through laboratory selection pressure using a continuing reduction of O2 over many generations. This phenotype is genetically stable sinceselected flies, after several generations in room air, survive at this low O2 level. Gene expression profiling showed striking differences between tolerant and na?¨ve flies, in larvae and adults, both quantitatively and qualitatively. Up-regulated genes in the tolerant flies included signal transduction pathways (e.g., Notch and Toll/Imd pathways),butmetabolicgeneswereremarkablydown-regulatedinthelarvae.Furthermore,adifferentallelicfrequency and enzymatic activity of the triose phosphate isomerase (TPI) was present in the tolerant versus na?¨ve flies. The transcriptional suppressor, hairy, was up-regulated