Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling.
Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling.
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DOI：
10.1371/journal.pone.0062215
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Minoo P
中科院分区：
文献类型：
--
作者：
Li A;Chan B;Felix JC;Xing Y;Li M;Brody SL;Borok Z;Li C;Minoo P
控制决定祖细胞/干细胞增殖与分化的分子信号尚未完全了解。运动纤毛从祖细胞/干细胞的分化可能提供一个简单易行的模型来研究这一过程。Wnt和Notch代表了许多组织中祖细胞/干细胞行为的两个关键信号通路。大肠腺瘤性息肉病，Apc是Wnt通路的负调节因子，是一种众所周知的多功能蛋白。使用cre-LoxP系统，我们通过Foxj 1-cre灭活Apc基因座，Foxj 1-cre在定向成纤毛细胞谱系的细胞中表达。然后，我们在两个选择的组织，承担运动纤毛，肺和睾丸的特点随之而来的表型。在肺中，Apc缺失诱导纤毛细胞中β-连环蛋白积累和Jag 1表达，并通过侧向诱导，触发邻近Clara细胞中的Notch信号传导。在细支气管上皮细胞中，Apc的缺乏阻断了致力于纤毛发生程序的细胞亚群的分化。在人肺腺癌细胞中，Apc过表达抑制了Jag 1的表达，并促进了包括Foxj 1在内的运动纤毛基因的表达，揭示了其可能的机制。在睾丸中，Apc失活诱导精原细胞中β-catenin积累，但Notch信号沉默，精原干细胞耗竭，与增殖减少相关，导致男性不育。总之，本比较分析揭示了通过协调Wnt和Notch信号传导，Apc失活对纤毛细胞祖细胞增殖和分化的组织依赖性后果。
The molecular signals that control decisions regarding progenitor/stem cell proliferation versus differentiation are not fully understood. Differentiation of motile cilia from progenitor/stem cells may offer a simple tractable model to investigate this process. Wnt and Notch represent two key signaling pathways in progenitor/stem cell behavior in a number of tissues. Adenomatous Polyposis Coli, Apc is a negative regulator of the Wnt pathway and a well known multifunctional protein. Using the cre-LoxP system we inactivated the Apc locus via Foxj1-cre, which is expressed in cells committed to ciliated cell lineage. We then characterized the consequent phenotype in two select tissues that bear motile cilia, the lung and the testis. In the lung, Apc deletion induced β-catenin accumulation and Jag1 expression in ciliated cells and by lateral induction, triggered Notch signaling in adjacent Clara cells. In the bronchiolar epithelium, absence of Apc blocked the differentiation of a subpopulation of cells committed to the ciliogenesis program. In the human pulmonary adenocarcinoma cells, Apc over-expression inhibited Jag1 expression and promoted motile ciliogenic gene expression program including Foxj1, revealing the potential mechanism. In the testis, Apc inactivation induced β-catenin accumulation in the spermatogonia, but silenced Notch signaling and depleted spermatogonial stem cells, associated with reduced proliferation, resulting in male infertility. In sum, the present comparative analysis reveals the tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors by coordinating Wnt and Notch signaling.
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影响因子：
4.5
作者：
通讯作者：
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.1005998107
发表时间：
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影响因子：
11.1
作者：
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通讯作者：
Drummond, Iain A.
DOI：
10.1073/pnas.1003462107
发表时间：
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影响因子：
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作者：
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