title: Sox9 induction, ectopic Paneth cells, and mitotic spindle axis defects in mouse colon adenomatous epithelium arising from conditional biallelic Apc inactivation.
abstract: We generated transgenic mice in which human CDX2 gene elements control expression of a tamoxifen-regulated Cre protein (CDX2P-CreER(T2)) to allow for inducible gene targeting in intestinal epithelium. After tamoxifen dosing of CDX2P-CreER(T2) mice, Cre activity was detected in the distal ileal, cecal, colonic, and rectal epithelium, with selected crypt base, transit amplifying, and surface cells all capable of activating Cre function. Four weeks after tamoxifen dosing of CDX2P-CreER(T2) mice carrying a Cre-activated fluorescent reporter, single crypts were uniformly fluorescence positive or negative, reflecting Cre activation in crypt stem cells. Biallelic inactivation of the Apc tumor suppressor gene via the CDX2P-CreER(T2) transgene in colon epithelium led to acute alterations in cell proliferation, apoptosis, and morphology, along with mitotic spindle misorientation, β-catenin nuclear localization, and induction of the intestinal stem cell markers Lgr5 and Musashi-1 and the Sox9 transcription factor. Normal mouse colon epithelium lacks Paneth cells, a key small intestine niche cell type, and Paneth cell differentiation is dependent on Sox9 function. In Apc-deficient colon epithelium, ectopic Paneth-like cells were seen outside the crypt base, such as new crypt budding sites. Our data indicate Apc inactivation via CDX2P-CreER(T2) targeting in mouse colon epithelium is sufficient to induce adenomatous changes and the generation of Paneth-like cells from neoplastic progenitors, with potentially significant roles in colon adenoma development and progression.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wiese
authors.forename: Evan
authors.initials: E
authors.lastname: Sands
authors.forename: Maranne
authors.initials: M
authors.lastname: Green
authors.forename: Guido T
authors.initials: GT
authors.lastname: Bommer
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000071616:CDX2 Transcription Factor; D020868:Gene Silencing / Q000502:physiology*; D017491:Genes, APC / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019879:Paneth Cells / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D008941:Spindle Apparatus / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D055758:SOX9 Transcription Factor; D014157:Transcription Factors; D013629:Tamoxifen