Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch
Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch
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DOI：
10.1242/dev.107714
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发表时间：
2015-01-01
期刊：
影响因子：
4.6
通讯作者：
Espinosa, Lluis
中科院分区：
文献类型：
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作者：
Lopez-Arribillaga, Erika;Rodilla, Veronica;Espinosa, Lluis
遗传数据表明，Notch-Rbpj或Wnt-β-catenin途径的取消会导致肠道干细胞(ISCs)的丧失。然而，Notch的作用是直接的，还是由于传递放大细胞向有丝分裂后杯状细胞的异常分化所致，目前尚不清楚。为了解决这个问题，我们建立了三苯氧胺诱导的肠道特异性遗传小鼠模型，并分析了肠道分化标志物的表达。重要的是，我们发现β-连环蛋白的激活部分挽救了Rbpj缺失突变体的分化表型，但不能挽救ISC间隔室的丢失。此外，我们还发现在ISC和前体细胞中表达的Bmi1基因是一个受Notch和β-catenin共同调节的基因。Bmi1的缺失导致ISC间隔室的增殖减少，伴随着p16(INK4a)和p19(ARF)(CDK2a的剪接变体)的积累，并增加向有丝分裂后杯状细胞系的分化，部分模仿Notch功能丧失缺陷。最后，我们提供了Bmi1有助于ISC自我更新的证据。
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.