Tsukushi functions as a Wnt signaling inhibitor by competing with Wnt2b for binding to transmembrane protein Frizzled4
Tsukushi functions as a Wnt signaling inhibitor by competing with Wnt2b for binding to transmembrane protein Frizzled4
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DOI：
10.1073/pnas.1100513108
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发表时间：
2011-09-06
影响因子：
11.1
通讯作者：
Tanaka, Hideaki
中科院分区：
文献类型：
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作者：
Ohta, Kunimasa;Ito, Ayako;Tanaka, Hideaki
Wnt信号通路是胚胎发育过程中多种组织发育所必需的信号通路。信号转导是通过Wnt蛋白与I型受体低密度脂蛋白受体相关蛋白5/6和七遍跨膜蛋白FrizzledFZD结合而激活的，FZD含有一个半胱氨酸富含结构域的WNT结合位点。已知的Wnt信号通路的胞外拮抗剂可以根据它们主要与Wnt结合还是与低密度脂蛋白受体相关蛋白5/6结合而分为两大类。我们发现分泌蛋白Tsukushi(TSK)通过与Fzd4的富含半胱氨酸的结构域直接结合而发挥Wnt信号抑制作用，亲和力为2.3×10(-10)M，并与Wnt2b竞争。在发育中的鸡眼中，TSK在睫状体/虹膜上皮细胞中表达，而Wnt2b在邻近的视泡前缘表达，在那里它控制着眼睛周围结构的分化，如睫状体和虹膜。TSK的过表达在体内和体外都能有效地拮抗鸡胚胎视网膜细胞中的Wnt2b信号，并抑制Wnt依赖的外眼命运的指定。相反，小鼠TSK基因的靶向失活会导致睫状体扩张，并上调发育中的周边眼Wnt2b和Fzd4的表达。因此，我们发现TSK作为一种Wnt信号抑制因子在调节外周眼球的形成中起着至关重要的作用。
The Wnt signaling pathway is essential for the development of diverse tissues during embryogenesis. Signal transduction is activated by the binding of Wnt proteins to the type I receptor low-density lipoprotein receptor-related protein 5/6 and the seven-pass transmembrane protein Frizzled (Fzd), which contains a Wnt-binding site in the form of a cysteine-rich domain. Known extracellular antagonists of the Wnt signaling pathway can be subdivided into two broad classes depending on whether they bind primarily to Wnt or to low-density lipoprotein receptor-related protein 5/6. We show that the secreted protein Tsukushi (TSK) functions as a Wnt signaling inhibitor by binding directly to the cysteine-rich domain of Fzd4 with an affinity of 2.3 x 10(-10) M and competing with Wnt2b. In the developing chick eye, TSK is expressed in the ciliary/iris epithelium, whereas Wnt2b is expressed in the adjacent anterior rim of the optic vesicle, where it controls the differentiation of peripheral eye structures, such as the ciliary body and iris. TSK overexpression effectively antagonizes Wnt2b signaling in chicken embryonic retinal cells both in vivo and in vitro and represses Wnt-dependent specification of peripheral eye fates. Conversely, targeted inactivation of the TSK gene in mice causes expansion of the ciliary body and up-regulation of Wnt2b and Fzd4 expression in the developing peripheral eye. Thus, we uncover a crucial role for TSK as a Wnt signaling inhibitor that regulates peripheral eye formation.