Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine.
Loss of Apc appears to be one of the major events initiating colorectal cancer. However, the first events responsible for this initiation process are not well defined and the ways in which different epithelial cell types respond to Apc loss are unknown. We used a conditional gene-ablation approach in transgenic mice expressing tamoxifen-dependent Cre recombinase all along the crypt-villus axis to analyze the immediate effects of Apc loss in the small intestinal epithelium, both in the stem-cell compartment and in postmitotic epithelial cells. Within 4 days, Apc loss induced a dramatic enlargement of the crypt compartment associated with intense cell proliferation, apoptosis and impairment of cell migration. This result confirms the gatekeeper role of Apc in the intestinal epithelium in vivo. Although Apc deletion activated beta-catenin signaling in the villi, we observed neither proliferation nor morphological change in this compartment. This highlights the dramatic difference in the responses of immature and differentiated epithelial cells to aberrant beta-catenin signaling. These distinct biological responses were confirmed by molecular analyses, revealing that Myc and cyclin D1, two canonical beta-catenin target genes, were induced in distinct compartments. We also showed that Apc is a crucial determinant of cell fate in the murine intestinal epithelium. Apc loss perturbs differentiation along the enterocyte, goblet and enteroendocrine lineages, and promotes commitment to the Paneth cell lineage through beta-catenin/Tcf4-mediated transcriptional control of specific markers of Paneth cells, the cryptdin/defensin genes.
Andreu
Pauline
P
Institut Cochin, INSERM U567, CNRS UMR8104, Université Paris V, 24 rue du Fb St-Jacques, 75014 Paris, France.
Colnot
Sabine
S
Godard
Cécile
C
Gad
Sophie
S
Chafey
Philippe
P
Niwa-Kawakita
Michiko
M
Laurent-Puig
Pierre
P
Kahn
Axel
A
Robine
Sylvie
S
Perret
Christine
C
Romagnolo
Béatrice
B
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000502:physiology; D023082:Defensins / Q000235:genetics / Q000378:metabolism; D017491:Genes, APC; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology; D007422:Intestines / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019879:Paneth Cells / Q000166:cytology / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D023082:Defensins; D011498:Protein Precursors; D015534:Trans-Activators; D051176:beta Catenin; C059569:cryptdin