Defining the impact of β-catenin/Tcf transactivation on epithelial stem cells
Defining the impact of β-catenin/Tcf transactivation on epithelial stem cells
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DOI：
10.1101/gad.1324905
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发表时间：
2005-07-01
影响因子：
10.5
通讯作者：
Fuchs, E
中科院分区：
文献类型：
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作者：
Lowry, WE;Blanpain, C;Fuchs, E
Wnt信号传导与干细胞（SC）生物学有关，但对于稳定的p -连环蛋白如何在原生SC生态位中发挥作用知之甚少。我们通过定义β -连环蛋白稳定性对多能卵泡SCs在其原生生态位和培养中的维持、增殖和谱系承诺的影响来解决这个问题。我们利用功能突变的增益和诱导功能突变的损失来证明β -连环蛋白的稳定对于促进SC静止和向增殖转运扩增（TA）后代的转化是必不可少的。我们对静息状态和激活状态下从野生型和升高的p-catenin卵泡中直接分离的sc进行转录分析，以揭示在天然sc中表达依赖于p-catenin稳定的离散基因集。最后，我们研究了潜在的机制，并表明在SC生态位中，Wnt信号传导和β -连环蛋白稳定可瞬间激活Lef1/Tcf复合物，并促进其与促进TA细胞转化和增殖的靶基因结合，形成新发育毛囊的活化细胞。我们还表明，这些变化先于随后影响TA后代的Wnt信号，以确定卵泡的分化谱系。
Wnt signaling has been implicated in stem cell (SC) biology, but little is known about how stabilized P-catenin functions within native SC niches. We address this by defining the impact of beta-catenin stabilization on maintenance, proliferation, and lineage commitment of multipotent follicle SCs when in their native niche and in culture. We employ gain of function mutations and inducible loss of function mutations to demonstrate that beta-catenin stabilization is essential for promoting the transition between SC quiescence and conversion to proliferating transit amplifying (TA) progeny. We transcriptionally profile purified SCs isolated directly from wild-type and elevated p-catenin follicles in both resting and activated states to uncover the discrete set of genes whose expression in native SCs is dependent upon p-catenin stabilization. Finally, we address the underlying mechanism and show that in the SC niche, Wnt signaling and beta-catenin stabilization transiently activate Lef1/Tcf complexes and promote their binding to target genes that promote TA cell conversion and proliferation to form the activated cells of the newly developing hair follicle. We also show that these changes precede subsequent Wnt signals that impact on the TA progeny to specify the differentiation lineages of the follicle.