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

Erika López-Arribillaga; Verónica Rodilla; Luca Pellegrinet; Jordi Guiu; Mar Iglesias; Angel Carlos Roman; Susana Gutarra; Susana González; Pura Muñoz-Cánoves; Pedro Fernández-Salguero; Freddy Radtke; Anna Bigas; Lluís Espinosa

doi:10.1242/dev.107714

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

Erika López-Arribillaga, Verónica Rodilla, Luca Pellegrinet, Jordi Guiu, Mar Iglesias, Angel Carlos Roman, Susana Gutarra, Susana González, Pura Muñoz-Cánoves, Pedro Fernández-Salguero, Freddy Radtke, Anna Bigas^*, Lluís Espinosa

^*Corresponding author af dette arbejde

66 Citationer (Scopus)

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^INK4aand 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.

Originalsprog	Engelsk
Tidsskrift	Development (Cambridge)
Vol/bind	142
Udgave nummer	1
Sider (fra-til)	41-50
Antal sider	10
ISSN	0950-1991
DOI	https://doi.org/10.1242/dev.107714
Status	Udgivet - 1 jan. 2015
Udgivet eksternt	Ja

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López-Arribillaga, E., Rodilla, V., Pellegrinet, L., Guiu, J., Iglesias, M., Roman, A. C., Gutarra, S., González, S., Muñoz-Cánoves, P., Fernández-Salguero, P., Radtke, F., Bigas, A., & Espinosa, L. (2015). Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development (Cambridge), 142(1), 41-50. https://doi.org/10.1242/dev.107714

López-Arribillaga, E, Rodilla, V, Pellegrinet, L, Guiu, J, Iglesias, M, Roman, AC, Gutarra, S, González, S, Muñoz-Cánoves, P, Fernández-Salguero, P, Radtke, F, Bigas, A & Espinosa, L 2015, 'Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch', Development (Cambridge), bind 142, nr. 1, s. 41-50. https://doi.org/10.1242/dev.107714

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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 p16INK4aand p19ARF(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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author = "Erika L{\'o}pez-Arribillaga and Ver{\'o}nica Rodilla and Luca Pellegrinet and Jordi Guiu and Mar Iglesias and Roman, {Angel Carlos} and Susana Gutarra and Susana Gonz{\'a}lez and Pura Mu{\~n}oz-C{\'a}noves and Pedro Fern{\'a}ndez-Salguero and Freddy Radtke and Anna Bigas and Llu{\'i}s Espinosa",

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doi = "10.1242/dev.107714",

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AU - López-Arribillaga, Erika

AU - Rodilla, Verónica

AU - Pellegrinet, Luca

AU - Guiu, Jordi

AU - Iglesias, Mar

AU - Roman, Angel Carlos

AU - Gutarra, Susana

AU - González, Susana

AU - Muñoz-Cánoves, Pura

AU - Fernández-Salguero, Pedro

AU - Radtke, Freddy

AU - Bigas, Anna

AU - Espinosa, Lluís

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N2 - 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 p16INK4aand p19ARF(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.

AB - 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 p16INK4aand p19ARF(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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Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch

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