Wnt-Frizzled Signaling Is Part of an FGF-Induced Cascade that Promotes Lens Fiber Differentiation
Wnt-Frizzled Signaling Is Part of an FGF-Induced Cascade that Promotes Lens Fiber Differentiation
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DOI：
10.1167/iovs.12-11357
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发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
McAvoy, John W.
中科院分区：
文献类型：
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作者：
Dawes, Lucy J.;Sugiyama, Yuki;McAvoy, John W.
目的。众所周知，晶状体纤维的分化依赖于fgf启动的生长因子信号级联。鉴于最近的研究表明Wnt-Frizzled/Planar Cell Polarity （Wnt-Fz/PCP）信号通路在协调纤维的定向和排列中起作用，本研究旨在探讨该通路与fgf诱导的纤维分化之间的关系。用FGF-2培养大鼠晶状体上皮组织。Wnt- fz信号的调节因子、分泌卷曲相关蛋白-1 （frp1）和Wnt产生-2抑制剂（IWP-2）被用于评估该通路在fgf诱导的纤维分化中的作用。使用TCF/ left报告小鼠评估典型Wnt-Fz/b-catenin信号。fgf诱导的纤维分化伴随着Wnt-Fz信号成分Fz3、Fz6、disheveled -2 （Dvl2）和disheveled -3的上调。在分化过程中，Fz和中心体/初级纤毛转移到类似极化的细胞群的顶尖/前缘。在fgf处理的外植体中添加strp1或IWP-2抑制了细胞伸长，并降低了纤维特异性标记物、filensin和β -crystallin的表达。Wnt-Fz信号组分的表达也减少，活性形式Dvl2的显著减少表明该途径受到抑制。对TCF/Lef报告小鼠的分析显示，在fgf诱导的纤维分化过程中没有典型的Wnt-Fz/b-catenin信号传导。这项研究表明，Wnt-Fz信号是fgf启动的调节纤维分化级联的一个组成部分。Fz和中心体/初级纤毛向每个细胞的前沿极化的纤维群的存在与非规范Wnt-Fz信号在协调分化纤维的极化行为中的作用是一致的。（Invest Ophthalmol Vis Sci. 2013;54:1582-1590） DOI: 10.1167/iovs.12-11357
PURPOSE. It is well established that lens fiber differentiation depends on an FGF-initiated growth factor signaling cascade. Given that recent studies indicate Wnt-Frizzled/Planar Cell Polarity (Wnt-Fz/PCP) signaling has a role in coordinating the orientation and alignment of fibers, this study set out to investigate the relationship between this pathway and FGF-induced fiber differentiation.METHODS. Rat lens epithelial explants were cultured with FGF-2. Regulators of Wnt-Fz signaling, secreted frizzled-related protein-1 (Sfrp1), and inhibitor of Wnt production-2 (IWP-2) were applied to assess the role of this pathway in FGF-induced fiber differentiation. A TCF/Lef reporter mouse was used to assess canonical Wnt-Fz/b-catenin signaling.RESULTS. FGF-induced fiber differentiation was accompanied by upregulation of Wnt-Fz signaling components, Fz3, Fz6, Dishevelled-2 (Dvl2), and Dishevelled-3. During differentiation, Fz and the centrosome/primary cilium translocated to the apical tip/leading edge of similarly polarized groups of cells. Addition of Sfrp1 or IWP-2 to FGF-treated explants inhibited cell elongation and reduced expression of fiber-specific markers, filensin and beta-crystallin. Expression of Wnt-Fz signaling components was also reduced and a significant reduction in the active form of Dvl2 indicated inhibition of the pathway. Analysis of the TCF/Lef reporter mouse showed no evidence of canonical Wnt-Fz/b-catenin signaling during FGF-induced fiber differentiation.CONCLUSIONS. This study shows that Wnt-Fz signaling is a component of the FGF-initiated cascade that regulates fiber differentiation. The presence of groups of fibers with Fz and centrosome/primary cilium polarized to the leading edge of each cell is consistent with a role for noncanonical Wnt-Fz signaling in coordinating polarized behavior of differentiating fibers. (Invest Ophthalmol Vis Sci. 2013;54:1582-1590) DOI: 10.1167/iovs.12-11357