title: Id2 controls specification of Lgr5+intestinal stem cell progenitors during gut development.
abstract: The adult intestinal stem cells (ISCs), their hierarchies, mechanisms of maintenance and differentiation have been extensively studied. However, when and how ISCs are established during embryogenesis remains unknown. We show here that the transcription regulator Id2 controls the specification of embryonic Lgr5+progenitors in the developing murine small intestine. Cell fate mapping analysis revealed that Lgr5+progenitors emerge at E13.5 in wild-type embryos and differ from the rest on the intestinal epithelium by a characteristic ISC signature. In the absence of Id2, the intestinal epithelium differentiates into Lgr5+cells already at E9.5. Furthermore, the size of the Lgr5+cell pool is significantly increased. We show that Id2 restricts the activity of the Wnt signalling pathway at early stages and prevents precocious differentiation of the embryonic intestinal epithelium. Id2-deficient embryonic epithelial cells culturedex vivostrongly activate Wnt target genes as well as markers of neoplastic transformation and form fast growing undifferentiated spheroids. Furthermore, adult ISCs from Id2-deficient mice display a distinct transcriptional signature, supporting an essential role for Id2 in the correct specification of ISCs.
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Lira
authors.initials: L
authors.lastname: Nigmatullina
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Maxim
authors.initials: M
authors.lastname: Norkin
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Dzama
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Berith
authors.initials: B
authors.lastname: Messner
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.affiliation: Institute of Molecular Biology, Mainz, Germany n.soshnikova@imb-mainz.de.
authors.forename: Natalia
authors.identifier: 0000-0002-4620-3669
authors.initials: N
authors.lastname: Soshnikova
mesh_terms: D000818:Animals; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D007421:Intestine, Small / Q000196:embryology*; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000032:analysis*; D013234:Stem Cells / Q000737:chemistry* / Q000502:physiology*; D060449:Wnt Signaling Pathway
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: ISC transcriptional signature; Wnt signalling; epithelial neoplasia; intestinal organoids; small intestine