期刊
DEVELOPMENT
卷 142, 期 1, 页码 41-50出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.107714
关键词
Notch; beta-catenin; Intestinal stem cells; Bmi1; Self-renewal
资金
- Instituto de Salud Carlos III [PI10/01128]
- Ministerio de Ciencia e Innovacion [ACI2009-0918]
- Agencia de Gestio d'Ajuts Universitaris i de Recerca-Convocatoria Estrategica [2010-0006]
- Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020/0098, RD12/0036/0054]
- Mar Institute of Medical Research (IMIM) Foundation
- European Molecular Biology Organization (EMBO) [ASTF 20-2010]
- Fundacio'n la Caixa
- Department of Education, Universities and Research of the Basque Government [BFI-2011]
- ICREA Funding Source: Custom
Genetic data indicate that abrogation of Notch-Rbpj or Wnt-beta-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 beta-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 beta-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.
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