title: Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine.
abstract: In the development of the mammalian intestine, Notch and Wnt/β-catenin signals control stem cell maintenance and their differentiation into absorptive and secretory cells. Mechanisms that regulate differentiation of progenitors into the three secretory lineages, goblet, paneth, or enteroendocrine cells, are not fully understood. Using conditional mutagenesis in mice, we observed that Shp2-mediated MAPK signaling determines the choice between paneth and goblet cell fates and also affects stem cells, which express the leucine-rich repeat-containing receptor 5 (Lgr5). Ablation of the tyrosine phosphatase Shp2 in the intestinal epithelium reduced MAPK signaling and led to a reduction of goblet cells while promoting paneth cell development. Conversely, conditional mitogen-activated protein kinase kinase 1 (Mek1) activation rescued the Shp2 phenotype, promoted goblet cell and inhibited paneth cell generation. The Shp2 mutation also expanded Lgr5+ stem cell niches, which could be restricted by activated Mek1 signaling. Changes of Lgr5+ stem cell quantities were accompanied by alterations of paneth cells, indicating that Shp2/MAPK signaling might affect stem cell niches directly or via paneth cells. Remarkably, inhibition of MAPK signaling in intestinal organoids and cultured cells changed the relative abundance of Tcf4 isoforms and by this, promoted Wnt/β-catenin activity. The data thus show that Shp2-mediated MAPK signaling controls the choice between goblet and paneth cell fates by regulating Wnt/β-catenin activity.
authors.affiliation: Laboratory of Signal Transduction in Development and Cancer and Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Heuberger
authors.forename: Frauke
authors.initials: F
authors.lastname: Kosel
authors.forename: Jingjing
authors.initials: J
authors.lastname: Qi
authors.forename: Katja S
authors.initials: KS
authors.lastname: Grossmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D020397:Goblet Cells / Q000166:cytology / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000166:cytology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009924:Organ Culture Techniques; D019879:Paneth Cells / Q000166:cytology / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; D020929:Mitogen-Activated Protein Kinase Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: Mek1DD; PTPN11; RTK; TCF7L2; crypt