A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness.
A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness.
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全肠上皮中有靶向肌肉表达的小鼠模型表明在细胞周期和干性中的调节作用。
DOI：
10.1002/stem.2202
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Plateroti M
中科院分区：
文献类型：
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作者：
Cambuli FM;Correa BR;Rezza A;Burns SC;Qiao M;Uren PJ;Kress E;Boussouar A;Galante PA;Penalva LO;Plateroti M
肠上皮因其持续的细胞更新而非常特殊，由定位于Lieberkühn隐窝内的多能干细胞提供动力。一些证据表明，进化保守的RNA结合蛋白Musashi1是包括肠上皮细胞在内的成体干细胞的标志，并揭示了它在干细胞自我更新和细胞命运决定中的作用。我们实验室以前的研究表明，Musashi1在髓母细胞瘤、胶质母细胞瘤和乳腺癌细胞中控制干细胞样特征，并在体外培养的肠上皮祖细胞中具有促增殖和促肿瘤特性。为了对Musashi1在体内肠上皮细胞中的S功能进行详细的研究，我们建立了一种小鼠模型，称为v-MSI，在整个肠上皮中特异性地过表达Musashi1。与野生型小鼠相比，v-Msi1小鼠表现出肠隐窝大小增加和增殖增强。RNA-seq的比较转录组学结果显示，武藏1‘S与肠道干细胞特征、细胞周期、DNA复制和药物代谢有关。最后，我们鉴定并验证了Musashi1、Ccnd1(Cyclin D1)、CDK6和Sox4稳定的三个新的mRNA靶点。综上所述，Musashi1在体内肠道上皮细胞中的靶向表达增加了细胞的增殖率，并强烈提示其对干细胞活性的作用。这是由于基因功能和途径的复杂网络的调节，包括药物代谢、细胞周期和DNA合成和修复。
The intestinal epithelium is very peculiar for its continuous cell renewal, fuelled by multipotent stem cells localized within the crypts of Lieberkühn. Several lines of evidence have established the evolutionary conserved RNA-binding protein Musashi1 as a marker of adult stem cells, including those of the intestinal epithelium, and revealed its roles in stem cell self-renewal and cell fate determination. Previous studies from our laboratories have shown that Musashi1 controls stem cell-like features in medulloblastoma, glioblastoma and breast cancer cells, and has pro-proliferative and pro-tumorigenic properties in intestinal epithelial progenitor cells in vitro. In order to undertake a detailed study of Musashi1’s function in the intestinal epithelium in vivo, we have generated a mouse model, referred to as v-Msi, overexpressing Musashi1 specifically in the entire intestinal epithelium. Compared with wild type litters, v-Msi1 mice exhibited increased intestinal crypt size accompanied by enhanced proliferation. Comparative transcriptomics by RNA-seq revealed Musashi1’s association with gut stem cell signature, cell cycle, DNA replication and drug metabolism. Finally, we identified and validated three novel mRNA targets that are stabilized by Musashi1, Ccnd1 (Cyclin D1), Cdk6 and Sox4. In conclusion, the targeted expression of Musashi1 in the intestinal epithelium in vivo increases the cell proliferation rate and strongly suggests its action on stem cells activity. This is due to the modulation of a complex network of gene functions and pathways including drug metabolism, cell cycle and DNA synthesis and repair.