title: Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch.
abstract: Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal.
authors.affiliation: Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Erika
authors.initials: E
authors.lastname: López-Arribillaga
authors.affiliation: Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Rodilla
authors.affiliation: Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Pellegrinet
authors.affiliation: Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Guiu
authors.affiliation: Department of Pathology, Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Extremadura, Badajoz 06071, Spain.
authors.forename: Angel Carlos
authors.initials: AC
authors.lastname: Roman
authors.affiliation: Departament de Ciències Experimentals, Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Gutarra
authors.affiliation: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: González
authors.affiliation: Departament de Ciències Experimentals, Universitat Pompeu Fabra, Barcelona 08003, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08003, Spain.
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Cánoves
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Extremadura, Badajoz 06071, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernández-Salguero
authors.affiliation: Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.affiliation: Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain abigas@imim.es lespinosa@imim.es.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.affiliation: Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain abigas@imim.es lespinosa@imim.es.
authors.forename: Lluís
authors.initials: L
authors.lastname: Espinosa
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D006706:Homeostasis; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000378:metabolism; D007422:Intestines / Q000002:abnormalities / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D011518:Proto-Oncogene Proteins; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D051153:Wnt Proteins; D051176:beta Catenin; D063150:Polycomb Repressive Complex 1
keywords: Bmi1; Intestinal stem cells; Notch; Self-renewal; β-catenin