title: Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells.
abstract: Ribosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium.
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Stedman
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Beck-Cormier
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Le Bouteiller
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Raveux
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Vandormael-Pournin
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Coqueran
authors.affiliation: Genetics of Tumor Suppression, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Curie, Centre de recherche, Paris, France.|UPMC University Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Lejour
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Jarzebowski
authors.affiliation: Genetics of Tumor Suppression, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Curie, Centre de recherche, Paris, France.|UPMC University Paris 06, Paris, France.|CNRS UMR 3244, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Toledo
authors.affiliation: Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, Institut Curie, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Robine
authors.affiliation: Mouse Functional Genetics, Department of Developmental & Stem Cell Biology, Institut Pasteur, 25 rue du docteur Roux, Paris, France.|CNRS URA 2578, Paris, France.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-6405-2657
authors.initials: M
authors.lastname: Cohen-Tannoudji
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D020397:Goblet Cells / Q000166:cytology*; D017403:In Situ Hybridization; D007422:Intestines / Q000166:cytology*; D018345:Mice, Knockout; D001678:Organelle Biogenesis; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53