Sox2 Is Required for Maintenance and Differentiation of Bronchiolar Clara, Ciliated, and Goblet Cells 英文参考文献.docVIP

Sox2IsRequiredforMaintenanceandDifferentiationof BronchiolarClara,Ciliated,andGobletCells DavidH.Tompkins,Vale′rieBesnard,AlexanderW.Lange,SusanE.Wert,AngelaR.Keiser,AprilN. Smith,RichardLang,JeffreyA.Whitsett* Division of Pulmonary Biology in the Perinatal Institute and Division of Pediatric Ophthalmology, Cincinnati Children’s Hospital Medical Center and the University of CincinnatiCollegeofMedicine,Cincinnati,Ohio,UnitedStatesofAmerica Abstract Thebronchiolesofthemurinelungarelinedbyasimplecolumnarepitheliumcomposedofciliated,Clara,andgobletcells thattogethermediatebarrierfunction,mucociliaryclearanceandinnatehostdefense,vitalforpulmonaryhomeostasis.In thepresentwork,wedemonstratethatexpressionofSox2inClaracellsisrequiredforthedifferentiationofciliated,Clara, and goblet cells that line the bronchioles of the postnatal lung. The gene was selectively deleted in Clara cells utilizing Scgb1a1-Cre,causingtheprogressivelossofSox2inthebronchiolesduringperinatalandpostnataldevelopment.Therate of bronchiolar cell proliferation was decreased and associated with the formation of an undifferentiated, cuboidal- squamous epithelium lacking the expression of markers of Clara cells (Scgb1a1), ciliated cells (FoxJ1 and a-tubulin), and gobletcells(SpdefandMuc5AC).Byadulthood,bronchiolarcellnumbersweredecreasedandSox2wasabsentinextensive regionsofthebronchiolarepithelium,atwhichtimeresidualSox2expressionwasprimarilyrestrictedtoselectivenichesof CGRPstainingneuroepithelialcells.Allergen-inducedgobletcelldifferentiationandmucusproductionwasabsentinthe respiratory epithelium lacking Sox2. In vitro, Sox2 activated promoter-luciferase reporter constructs for differentiation markerscharacteristicofClara,ciliated,andgobletcells,Scgb1a1,FoxJ1,andAgr2,respectively.Sox2physicallyinteracted with Smad3 and inhibited TGF-b1/Smad3-mediated transcriptional activity in vitro, a pathway that negatively regulates proliferation.Sox2isrequiredforproliferationanddifferentiationofClaracellsthatserveasth