TranscriptionfactorsinparathyroiddevelopmentGrigorieva&Thakker
aswellasanexpressionpatternthatoverlapswithPax1.97,98Pax9?/?micealsolackderivativesofthethirdandfourthpharyngealpouches,whichin-cludestheparathyroidsandthymus.98Pax3?/?em-bryos(Splotchembryos),whicharelargelyde?cientofneuralcrestcells,alsohavepharyngeal-pouchdefectsthatincludedelayedseparationoftheparathyroidandthymusfromthepharynxandanabnormalboundarybetweenthymusandparathyroid-fateddomains.99Theseresultsindicatethatneuralcrestcellmigrationtothethirdpharyn-gealpouchisimportantforpatterningandmorpho-genesisoftheparathyroidsandthymus.99PatientswithPAX1,PAX3,orPAX9mutationshavenotbeenreportedtodevelophypoparathyroidism.100–102TheEya1andSixgeneshavealsobeenshowntoregu-latethepatterninganddifferentiationofthethirdpharyngealpouchendodermintoparathyroidsandthymus.95Eya1isamammalianhomologueoftheDrosophilaeyesabsent(eya)gene,103andEYA1mu-tationsinmanareassociatedwiththecongenitalBranchio-oto-renal(BOR)syndrome,104whichischaracterizedbyhearingloss,branchialcysts,andrenalfailure.105,106Inmice,Eya1isstronglyex-pressedinthe?rst,second,third,andfourthpha-ryngealarches;inthesecond,third,andfourthpouchendoderm;andthepharyngealcleftecto-dermatE9.5–10.5,107aswellasinderivedstruc-tures,suchasthethymusandparathyroid.94ThisexpressionofEya1isconsistentwiththeobserveddefectsinEya1?/?mouseembryos,whichlackparathyroid/thymusprimordiathatresultsinab-sentparathyroidsandthymus,aswellasthyroidhypoplasia.94Inaddition,targetedinactivationofEya1causesimpairedearlydevelopmentofmul-tipleorgans,includingtheear,kidney,andskele-talsystem.108EYA1physicallyinteractswithSIXproteins,109,110andtheexpressionofSix1,whichencodesahomeodomainproteinhomologoustoDrosophilasineoculis(so)intheearlypharyngealendoderm,mesenchyme,andectoderm,isalsoEya1dependent.94SIX1mutationsinmanarealsoasso-ciatedwithBORsyndrome,95,111andSix1?/?micelackthethymusandparathyroids.95Interestingly,inSix1?/?mice,theendodermalcellsofthethy-mus/parathyroidrudimentsfailtomaintaintheex-pressionoftheparathyroid-speci?cgeneGcm2andthethymus-speci?cgeneFoxn1,bothofwhichun-dergoapoptosisthatleadstothecompletedisap-pearanceoftheseorganprimordiabyE12.5,thereby,
indicatingthatGcm2maybeadownstreamtargetofSix1.StudiesoftheseknockoutmicehavealsodemonstratedthatEya1isrequiredfortheinitia-tionofthymus/parathyroidorganogenesis,whereasSix1isrequiredfordifferentiation,95andstudiesus-ingaEya:Six1doublemutanthavedemonstratedalossofPax1inthepharyngealendoderm,indicatingthatPax1isdownstreamofEya1-Six,whereasthecontinuedexpressionofPax9hasindicatedthatitfunctionsinparallelorindependentlyfromEya1-Sixinthepharyngealendoderm.95TherelationshipbetweenEya1-Six1andHoxa3hasalsobeenstudied,anditseemsthatHoxa3mayfunctionupstreamorinparallelwithEya1-Sixtoregulatetheexpressionoforgan-speci?cgenesGcm2andFoxn1aswellasotherpatterninggenes.95Conclusion
Studiesofpatientswithhypoparathyroidismandmicewithparathyroiddefectshaveelucidatedim-portantrolesindeterminingthedifferentiationofpharyngealpouchcellsintoparathyroidcellsforanumberoftranscriptionfactors,includingTbx1,Gata3,Gcm2,Sox3,Aire1andmembersoftheHoxandPaxfamilies.Acknowledgments
TheauthorsthanktheMedicalResearchCouncil(MRC),UKforsupport(GrantnumberG1000467,2010).
Con?ictsofinterest
Theauthorsdeclarenocon?ictsofinterest.References
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