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

Significance statement

Active Notch and Wnt/β-catenin signaling are both required to ensure transcription of Bmi1 in the intestinal stem and progenitor cell compartments. In homeostasis, loss of Bmi1 recapitulates some Notch-loss-of-function defects including reduced proliferation and defective DNA-damage repair. Nonetheless, the clinical and pathological relevance of Bmi1 and other specific effectors of these signaling pathways in disease remains unexplored. This work identifies important elements downstream of Notch and Wnt/β-catenin that, when applied to particular cancer systems, should provide novel therapeutic opportunities much less deleterious than the general inhibitors that are currently being used.

Figure Legend

Detection of cleaved (active) Notch 1 (green) and Bmi1 (red) proteins in the developing murine intestine, at the onset of villogenesis (E15.5). Nuclei are counterstained with DAPI (blue).

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

 

 

 

 

 

 

 

 

 

Journal Reference

López-Arribillaga E1, Rodilla V1, Pellegrinet L2, Guiu J1, Iglesias M3, Roman AC4, Gutarra S5, González S6, Muñoz-Cánoves P7, Fernández-Salguero P4,Radtke F2, Bigas A8, Espinosa L8.

Development. 2015 ;142(1):41-50.

Show Affiliations

1Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain.and

2Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland.and

3Department of Pathology, Hospital del Mar, Barcelona 08003, Spain.and

4Department of Biochemistry and Molecular Biology, University of Extremadura, Badajoz 06071, Spain.and

5Departament de Ciències Experimentals, Universitat Pompeu Fabra, Barcelona 08003, Spain.and

6Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.and

7Departament de Ciències Experimentals, Universitat Pompeu Fabra, Barcelona 08003, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08003, Spain.and

8Program in Cancer Research, IMIM-Hospital del Mar, Barcelona 08003, Spain [email protected] [email protected]

 

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.

© 2015. Published by The Company of Biologists Ltd.

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