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Development. 2015 Jan 1;142(1):41-50. doi: 10.1242/dev.107714. Epub 2014 Dec 5.

Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch.

Author information

1
Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain.
2
Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland.
3
Department of Pathology, Hospital del Mar, Barcelona 08003, Spain.
4
Department of Biochemistry and Molecular Biology, University of Extremadura, Badajoz 06071, Spain.
5
Departament de Ciències Experimentals, Universitat Pompeu Fabra, Barcelona 08003, Spain.
6
Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
7
Departament de Ciències Experimentals, Universitat Pompeu Fabra, Barcelona 08003, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08003, Spain.
8
Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain abigas@imim.es lespinosa@imim.es.

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.

KEYWORDS:

Bmi1; Intestinal stem cells; Notch; Self-renewal; β-catenin

PMID:
25480918
DOI:
10.1242/dev.107714
[Indexed for MEDLINE]
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