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Affecting Rhomboid-3 Function Causes a Dilated Heart in Adult Drosophila 英文参考文献
AffectingRhomboid-3FunctionCausesaDilatedHeartin
AdultDrosophila
LinYu1,TeresaLee2,NaLin3,MatthewJ.Wolf1*
1DivisionofCardiology,DepartmentofMedicine,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica,2DepartmentofCellBiology,Duke
University,Durham,NorthCarolina,UnitedStatesofAmerica,3InstituteofMolecularMedicine,PekingUniversity,Beijing,China
Abstract
Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that
Drosophilacanbeused asamodelofhumanheart failure.Previously,wedescribedthatopticalcoherencetomography
(OCT)canbeusedtorapidlyexaminethecardiacfunctioninadult,awakeflies.Thistechniqueprovidesimagesthatare
similartoechocardiographyinhumans,andthereforewepostulatedthatthisapproachcouldbecombinedwiththevast
resourcesthatareavailableintheflycommunitytoidentifynewmutantsthathaveabnormalheartfunction,ahallmarkof
certaincardiovasculardiseases.UsingOCTtoexaminethecardiacfunctioninadultDrosophilafromasetofmolecularly-
defined genomic deficiencies from the DrosDel and Exelixis collections, we identified an abnormally enlarged cardiac
chamberinaseriesofdeficiencymutantsspanningtherhomboid3locus.Rhomboid3isamemberofahighlyconserved
familyofintramembraneserineproteasesandprocessesSpitz,anepidermalgrowthfactor(EGF)–likeligand.Usingmultiple
approaches based on the examination of deficiency stocks, a series of mutants in the rhomboid-Spitz–EGF receptor
pathway,andcardiac-specifictransgenicrescueordominant-negativerepressionofEGFR,wedemonstratethatrhomboid3
mediated activation of the EGF receptor pathway is necessary for proper adult cardiac function. The importance of EGF
receptor signaling in the adult Drosophila heart underscores the concept that evolutionarily conserved signaling
mechanismsarerequiredtomaintainnormalmyocardialfunction.Interestingly,priorworkshowingtheinhibitionofErbB2,
amemberoftheEGFreceptorfamily,intransgenicknock-outmiceorindividualsthatreceivedherceptinchemotherapyis
associa
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