title: Wnt signalling induces maturation of Paneth cells in intestinal crypts.
abstract: Wnt signalling, which is transduced through beta-catenin/TCF4, maintains the undifferentiated state of intestinal crypt progenitor cells. Mutational activation of the pathway initiates the adenomacarcinoma sequence. Whereas all other differentiated epithelial cells migrate from the crypt onto the villus, Paneth cells home towards the source of Wnt signals--that is, the crypt bottom. Here, we show that expression of a Paneth gene programme is critically dependent on TCF4 in embryonic intestine. Moreover, conditional deletion of the Wnt receptor Frizzled-5 abrogates expression of these genes in Paneth cells in the adult intestine. Conversely, adenomas in Apc-mutant mice and colorectal cancers in humans inappropriately express these Paneth-cell genes. These observations imply that Wnt signals in the crypt can separately drive a stem-cell/progenitor gene programme and a Paneth-cell maturation programme. In intestinal cancer, both gene programmes are activated simultaneously.
authors.affiliation: Hubrecht Institute, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Philippe
authors.initials: P
authors.lastname: Jay
authors.forename: Alex
authors.initials: A
authors.lastname: Gregorieff
authors.forename: Marielle E
authors.initials: ME
authors.lastname: van Gijn
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jonkheer
authors.forename: Pantelis
authors.initials: P
authors.lastname: Hatzis
authors.forename: Andrea
authors.initials: A
authors.lastname: Thiele
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.forename: Harry
authors.initials: H
authors.lastname: Begthel
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D000818:Animals; D002843:Chromatin / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007421:Intestine, Small / Q000166:cytology* / Q000196:embryology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D019879:Paneth Cells / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins
chemical_list: D002843:Chromatin; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins