Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB.
In the small intestine, the progeny of stem cells migrate in precise patterns. Absorptive, enteroendocrine, and goblet cells migrate toward the villus while Paneth cells occupy the bottom of the crypts. We show here that beta-catenin and TCF inversely control the expression of the EphB2/EphB3 receptors and their ligand ephrin-B1 in colorectal cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3 genes reveals that their gene products restrict cell intermingling and allocate cell populations within the intestinal epithelium. In EphB2/EphB3 null mice, the proliferative and differentiated populations intermingle. In adult EphB3(-/-) mice, Paneth cells do not follow their downward migratory path, but scatter along crypt and villus. We conclude that in the intestinal epithelium beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin-B system.
Batlle
Eduard
E
Department of Immunology and Center for Biomedical Genetics, University Medical Center, Utrecht, The Netherlands.
Henderson
Jeffrey T
JT
Beghtel
Harry
H
van den Born
Maaike M W
MM
Sancho
Elena
E
Huls
Gerwin
G
Meeldijk
Jan
J
Robertson
Jennifer
J
van de Wetering
Marc
M
Pawson
Tony
T
Clevers
Hans
H
D000199:Actins / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002451:Cell Compartmentation; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D036387:Ephrin-B1 / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D009419:Nerve Tissue Proteins; D019879:Paneth Cells / Q000166:cytology; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000199:Actins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D036387:Ephrin-B1; D036388:Ephrin-B2; D051821:Lymphoid Enhancer-Binding Factor 1; D009419:Nerve Tissue Proteins; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; C497576:TCF7 protein, human; C544894:TCF7L2 protein, human; C090743:Tcf4 protein, mouse; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D036081:Receptors, Eph Family