The Hippo signaling pathway regulates cell proliferation and organ growth, and its activation is mainly reflected by the phosphorylation levels of Yes-associated protein (YAP). In this study, we show that YAP facilitates embryonic neural stem cell proliferation by elevating their responsiveness to fibroblast growth factor 2 (FGF2), one of the major growth factors for neural stem cells, in vivo as well as in vitro. Western blot and quantitative real-time PCR analyses revealed that expression of the FGF receptors (FGFRs) FGFR1 to FGFR4 were greatly increased by YAP expression upon FGF2 treatment, followed by upregulation of the mitogen-activated protein kinase and protein kinase B signaling pathways. Furthermore, as assessed by quantitative real-time PCR analyses, YAP-induced FGFR expression was found to be TEA domain transcription factor (TEAD)-independent, and transcriptional coactivator with PDZ-binding motif, the other homolog of Yorki in the Drosophila Hippo signaling pathway, was found to possess similar activity to YAP. Finally, adjustment of FGFR signaling activity in the YAP-expressing cells to control levels efficiently offset the cell proliferative effects of YAP, suggesting that the increased proliferation of YAP-expressing neural stem cells was mainly attributable to enhanced FGFR signaling. Our data indicate that YAP plays an important role in neural stem cell regulation by elevating FGFR expression, subsequently leading to enhanced cell proliferation.

中文翻译：

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YAP 通过诱导 FGF 受体表达增强 FGF2 依赖性神经干细胞增殖。

Hippo 信号通路调节细胞增殖和器官生长，其激活主要体现在 Yes 相关蛋白 (YAP) 的磷酸化水平。在这项研究中，我们表明 YAP 通过提高胚胎神经干细胞对成纤维细胞生长因子 2 (FGF2) 的反应性来促进胚胎神经干细胞增殖，成纤维细胞生长因子 2 (FGF2) 是体内和体外神经干细胞的主要生长因子之一。蛋白质印迹和实时定量 PCR 分析显示 FGF 受体 (FGFRs) FGFR1到FGFR4 的表达因 FGF2 处理后的 YAP 表达而大大增加，随后是丝裂原活化蛋白激酶和蛋白激酶 B 信号通路的上调。此外，通过实时定量 PCR 分析评估，YAP 诱导的发现FGFR表达不依赖于 TEA 域转录因子 (TEAD)，并且发现具有 PDZ 结合基序（果蝇Hippo 信号通路中 Yorki 的另一个同源物）的转录共激活因子具有与 YAP 相似的活性。最后，将表达 YAP 的细胞中的 FGFR 信号活性调整到控制水平有效地抵消了 YAP 的细胞增殖作用，表明表达 YAP 的神经干细胞增殖的增加主要归因于增强的 FGFR 信号。我们的数据表明，YAP 通过提高 FGFR 表达在神经干细胞调节中发挥重要作用，随后导致细胞增殖增强。