A Critical Role for the Wnt Effector Tcf4 in Adult Intestinal Homeostatic Self-Renewal

A Critical Role for the Wnt Effector Tcf4 in Adult Intestinal Homeostatic Self-Renewal Johan H. van Es a , Andrea Haegebarth a , * , Pekka Kujala a , b , Shalev Itzkovitz c , Bon-Kyoung Koo a , Sylvia F. Boj a , Jeroen Korving a , Maaike van den Born a , Alexander van Oudenaarden c , Sylvie Robine d and Hans Clevers a a Hubrecht Institute for Developmental Biology and Stem Cell Research & University Medical Centre Utrecht, Utrecht, Netherlands b Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, Netherlands c Department of Physics & Biology, Massachusetts Institute of Technology, Cambridge Massachusetts, USA d Morphogenesis and Intracellular Signaling, Institut Curie-CNRS, Paris, France ABSTRACT Throughout life, intestinal Lgr5 + stem cells give rise to proliferating transient amplifying cells in crypts, which subsequently differentiate into one of the five main cell types and migrate along the crypt-villus axis. These dynamic processes are coordinated by a relatively small number of evolutionarily conserved signaling pathways, which includes the Wnt signaling pathway. The DNA-binding proteins of the T-cell factor family, Tcf1/Tcf7, Lef, Tcf3/Tcf7l1, and Tcf4/Tcf7l2, constitute the downstream effectors of the Wnt signaling pathway. While Tcf4 is the major member active during embryogenesis, the role of these Wnt effectors in the homeostasis of the adult mouse intestinal epithelium is unresolved. Using Tcf1 −/− , Tcf3 flox , and novel Tcf4 flox mice, we demonstrate an essential role for Tcf4 during homeostasis of the adult mouse intestine.