title: A Dynamic WNT/β-CATENIN Signaling Environment Leads to WNT-Independent and WNT-Dependent Proliferation of Embryonic Intestinal Progenitor Cells.
abstract: Much of our understanding about how intestinal stem and progenitor cells are regulated comes from studying the late fetal stages of development and the adult intestine. In this light, little is known about intestine development prior to the formation of stereotypical villus structures with columnar epithelium, a stage when the epithelium is pseudostratified and appears to be a relatively uniform population of progenitor cells with high proliferative capacity. Here, we investigated a role for WNT/β-CATENIN signaling during the pseudostratified stages of development (E13.5, E14.5) and following villus formation (E15.5) in mice. In contrast to the well-described role for WNT/β-CATENIN signaling as a regulator of stem/progenitor cells in the late fetal and adult gut, conditional epithelial deletion of β-catenin or the Frizzled co-receptors Lrp5 and Lrp6 had no effect on epithelial progenitor cell proliferation in the pseudostratified epithelium. Mutant embryos displayed obvious developmental defects, including loss of proliferation and disruptions in villus formation starting only at E15.5. Mechanistically, our data suggest that WNT signaling-mediated proliferation at the time of villus formation is driven by mesenchymal, but not epithelial, WNT ligand secretion.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Alana M
authors.initials: AM
authors.lastname: Chin
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yu-Hwai
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Stacy R
authors.initials: SR
authors.lastname: Finkbeiner
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Nagy
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Walker
authors.affiliation: Program in Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Ethen
authors.affiliation: Program in Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Battle
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: spencejr@umich.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Spence
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000196:embryology; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D055758:SOX9 Transcription Factor; D051153:Wnt Proteins; D051176:beta Catenin; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: WNT; development; epithelium; intestine; morphogenesis; progenitor cell; proliferation; stem cell; villus; β-CATENIN