title: Cdx2 determines the fate of postnatal intestinal endoderm.
abstract: Knock out of intestinal Cdx2 produces different effects depending upon the developmental stage at which this occurs. Early in development it produces histologically ordered stomach mucosa in the midgut. Conditional inactivation of Cdx2 in adult intestinal epithelium, as well as specifically in the Lgr5-positive stem cells, of adult mice allows long-term survival of the animals but fails to produce this phenotype. Instead, the endodermal cells exhibit cell-autonomous expression of gastric genes in an intestinal setting that is not accompanied by mesodermal expression of Barx1, which is necessary for gastric morphogenesis. Cdx2-negative endodermal cells also fail to express Sox2, a marker of gastric morphogenesis. Maturation of the stem cell niche thus appears to be associated with loss of ability to express positional information cues that are required for normal stomach development. Cdx2-negative intestinal crypts produce subsurface cystic vesicles, whereas untargeted crypts hypertrophy to later replace the surface epithelium. These observations are supported by studies involving inactivation of Cdx2 in intestinal crypts cultured in vitro. This abolishes their ability to form long-term growing intestinal organoids that differentiate into intestinal phenotypes. We conclude that expression of Cdx2 is essential for differentiation of gut stem cells into any of the intestinal cell types, but they maintain a degree of cell-autonomous plasticity that allows them to switch on a variety of gastric genes.
authors.affiliation: Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Stringer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Duluc
authors.forename: Thoueiba
authors.initials: T
authors.lastname: Saandi
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.forename: Monika
authors.initials: M
authors.lastname: Bialecka
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Nick
authors.initials: N
authors.lastname: Barker
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Catrin A
authors.initials: CA
authors.lastname: Pritchard
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Winton
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Freund
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Deschamps
authors.forename: Felix
authors.initials: F
authors.lastname: Beck
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004707:Endoderm / Q000254:growth & development*; D005260:Female; D005753:Gastric Mucosa / Q000254:growth & development; D055786:Gene Knockout Techniques; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000254:growth & development*; D007421:Intestine, Small / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: C095587:Barx1 protein, mouse; D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors