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

TY - JOUR

T1 - Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch

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

PY - 2015/1/1

Y1 - 2015/1/1

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.

KW - Bmi1

KW - Intestinal stem cells

KW - Notch

KW - Self-renewal

KW - β-catenin

UR - http://www.scopus.com/inward/record.url?scp=84918533766&partnerID=8YFLogxK

U2 - 10.1242/dev.107714

DO - 10.1242/dev.107714

M3 - Journal article

C2 - 25480918

AN - SCOPUS:84918533766

SN - 0950-1991

VL - 142

SP - 41

EP - 50

JO - Development (Cambridge)

JF - Development (Cambridge)

IS - 1

ER -