title: Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells.
abstract: Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis.
authors.affiliation: Department of Molecular & Integrative Physiology, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: VanDussen
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Carulli
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Keeley
authors.forename: Sanjeevkumar R
authors.initials: SR
authors.lastname: Patel
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Puthoff
authors.forename: Scott T
authors.initials: ST
authors.lastname: Magness
authors.forename: Ivy T
authors.initials: IT
authors.lastname: Tran
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Christian
authors.initials: C
authors.lastname: Siebel
authors.forename: Åsa
authors.initials: Å
authors.lastname: Kolterud
authors.forename: Ann S
authors.initials: AS
authors.lastname: Grosse
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Gumucio
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ernst
authors.forename: Yu-Hwai
authors.initials: YH
authors.lastname: Tsai
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dempsey
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D019879:Paneth Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C500943:Atoh1 protein, mouse; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse