title: Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1).
abstract: Intestinal epithelium has the capacity to self-renew and generate differentiated cells through the existence of two types of epithelial stem cells: active crypt base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells are regulated both by intrinsic programs and by extrinsic signals sent by neighboring cells, which define the niche. It is clear that the β-catenin pathway acts as an essential intrinsic signal for the maintenance and proliferation of CBC, and it was recently proposed that Paneth cells provide a crucial niche by secreting Wingless/Int (Wnt) ligands. Here, we examined the effect of disrupting the intestinal stem cell niche by inducible deletion of the transcription factor Math1 (Atoh1), an essential driver of secretory cell differentiation. We found that complete loss of Paneth cells attributable to Math1 deficiency did not perturb the crypt architecture and allowed the maintenance and proliferation of CBCs. Indeed, Math1-deficient crypt cells tolerated in vivo Paneth cell loss and maintained active β-catenin signaling but could not grow ex vivo without exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential niche. Upon irradiation, Math1-deficient crypt cells regenerated and CBCs continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis coli (Apc) and Math1 were able to promote intestinal tumorigenesis. We conclude that in vivo, Math1-deficient crypts counteract the absence of Paneth cell-derived Wnts and prevent CBC stem cell exhaustion.
authors.affiliation: Institut Cochin, Department of Endocrinology, Metabolism and Cancer,  Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, 75014 Paris,  France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Durand
authors.forename: Bridgitte
authors.initials: B
authors.lastname: Donahue
authors.forename: Grégory
authors.initials: G
authors.lastname: Peignon
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Christian
authors.initials: C
authors.lastname: Slomianny
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
authors.forename: Noah F
authors.initials: NF
authors.lastname: Shroyer
authors.forename: Béatrice
authors.initials: B
authors.lastname: Romagnolo
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000166:cytology*; D051379:Mice; D046228:Microarray Analysis; D008854:Microscopy, Electron; D019879:Paneth Cells / Q000166:cytology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000648:ultrastructure*; D051153:Wnt Proteins / Q000172:deficiency; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C500943:Atoh1 protein, mouse