Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine
Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine
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DOI：
10.1242/dev.01700
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发表时间：
2005-03-01
期刊：
影响因子：
4.6
通讯作者：
Romagnolo, B
中科院分区：
文献类型：
--
作者：
Andreu, P;Colnot, S;Romagnolo, B
Apc缺失似乎是引发结直肠癌的主要事件之一。然而，负责这一启动过程的第一个事件并没有很好地定义，不同的上皮细胞类型响应Apc损失的方式也是未知的。我们使用了一种条件性基因消融的方法，在转基因小鼠中表达他莫昔芬依赖性Cre重组酶所有沿着隐窝绒毛轴分析的直接影响APC损失的小肠上皮细胞，无论是在干细胞室和有丝分裂后的上皮细胞。在4天内，Ape损失诱导与强烈的细胞增殖、细胞凋亡和细胞迁移受损相关的隐窝隔室的急剧扩大。该结果证实了Apc在体内肠上皮中的看门人作用。虽然Apc缺失激活了绒毛中的β-连环蛋白信号，但我们在该隔室中既没有观察到增殖也没有观察到形态学变化。这突出了未成熟和分化的上皮细胞对异常β-连环蛋白信号传导的反应的显著差异。这些不同的生物学反应被分子分析证实，揭示了Myc和细胞周期蛋白D1，两个典型的P-连环蛋白靶基因，在不同的隔间诱导。我们还表明Apc是小鼠肠上皮细胞命运的关键决定因素。APC的丢失扰乱了肠上皮细胞、杯状细胞和肠内分泌细胞系的分化，并通过β-连环蛋白/Tcf 4介导的帕氏细胞特异性标志物（即隐球菌素/防御素基因）的转录控制促进了向帕氏细胞系的定型。
Loss of Apc appears to be one of the major events initiating colorectal, cancer. However, the first events responsible for this initiation process are not well defined and the ways in which different epithelial cell types respond to Apc loss are unknown. We used a conditional gene-ablation approach in transgenic mice expressing tamoxifen-dependent Cre recombinase all along the crypt-villus axis to analyze the immediate effects of Apc loss in the small intestinal epithelium, both in the stem-cell compartment and in postmitotic epithelial cells. Within 4 days, Ape loss induced a dramatic enlargement of the crypt compartment associated with intense cell proliferation, apoptosis and impairment of cell migration. This result confirms the gatekeeper role of Apc in the intestinal epithelium in vivo. Although Apc deletion activated beta-catenin signaling in the villi, we observed neither proliferation nor morphological change in this compartment. This highlights the dramatic difference in the responses of immature and differentiated epithelial cells to aberrant beta-catenin signaling. These distinct biological responses were confirmed by molecular analyses, revealing that Myc and cyclin D1, two canonical P-catenin target genes, were induced in distinct compartments. We also showed that Apc is a crucial determinant of cell fate in the murine intestinal epithelium. Apc loss perturbs differentiation along the enterocyte, goblet and enteroendocrine lineages, and promotes commitment to the Paneth cell lineage through beta-catenin/Tcf4-mediated transcriptional control of specific markers of Paneth cells, the cryptdin/defensin genes.