Loss of mismatch repair signaling impairs the WNT–bone morphogenetic protein crosstalk and the colonic homeostasis

作     者：Katrine Nørgaard Carolin Müller Nadja Christensen María L.Chiloeches Cesilie L.Madsen Sabine S.Nielsen Tine E.Thingholm Antoaneta Belcheva Katrine Nφrgaard;Carolin Müller;Nadja Christensen;María L.Chiloeches;Cesilie L.Madsen;Sabine S.Nielsen;Tine E.Thingholm;Antoaneta Belcheva

作者机构：Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkCampusvej 555230 Odense MDenmark Department of Molecular MedicineUniversity of Southern DenmarkJ.B.Winsløws Vej 255230 Odense MDenmark 

出 版 物：《Journal of Molecular Cell Biology》 (分子细胞生物学报（英文版）)

年 卷 期：2020年第12卷第6期

页      面：410-423页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：This project is funded by the Department of Biochemistry and Molecular Biology at University of Southern Denmark 

主　　题：MMR colonic epithelium WNT BMP crypt homeostasis 

摘      要：The fine balance between proliferation,differentiation,and apoptosis in the colonic epithelium is tightly controlled by the interplay between WNT,Notch,and bone morphogenetic protein(BMP)*** these complex networks coordinate the colonic homeostasis,especially if cancer predisposing mutations such as mutations in the DNA mismatch repair(MMR)are present,is *** of the MMR system has long been linked to colorectal cancer;however,little is known about its role in the regulation of the colonic *** has been shown that loss of MMR promotes the proliferation of colon epithelial cells that renders them highly susceptible to *** mechanism through which MMR mediates this effect,yet,remains to be *** an MMR-deficient mouse model,we show that increased methylation of Dickkopf1 impacts its expression,and consequently,the ability to negatively regulate WNT *** a result,excessive levels of activeβ-catenin promote strong crypt progenitor-like phenotype and abnormal *** these settings,the development and function of the goblet cells are ***-deficient mice have fewer goblet cells with enlarged mucin-loaded *** further show that MMR inactivation impacts the WNT–BMP signaling crosstalk.