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 

机构地区：[1]Department of Biochemistry and Molecular Biology,University of Southern Denmark,Campusvej 55,5230 Odense M,Denmark [2]Department of Molecular Medicine,University of Southern Denmark,J.B.Winsløws Vej 25,5230 Odense M,Denmark

出　　处：《Journal of Molecular Cell Biology》2020年第6期410-423,共14页分子细胞生物学报（英文版）

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

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)signaling.How these complex networks coordinate the colonic homeostasis,especially if cancer predisposing mutations such as mutations in the DNA mismatch repair(MMR)are present,is unclear.Inactivation of the MMR system has long been linked to colorectal cancer;however,little is known about its role in the regulation of the colonic homeostasis.It has been shown that loss of MMR promotes the proliferation of colon epithelial cells that renders them highly susceptible to transformation.The mechanism through which MMR mediates this effect,yet,remains to be determined.Using an MMR-deficient mouse model,we show that increased methylation of Dickkopf1 impacts its expression,and consequently,the ability to negatively regulate WNT signaling.As a result,excessive levels of activeβ-catenin promote strong crypt progenitor-like phenotype and abnormal proliferation.Under these settings,the development and function of the goblet cells are affected.MMR-deficient mice have fewer goblet cells with enlarged mucin-loaded vesicles.We further show that MMR inactivation impacts the WNT–BMP signaling crosstalk.

关 键 词：MMR colonic epithelium WNT BMP crypt homeostasis 

分 类 号：R574[医药卫生—消化系统]