Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina.
Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina.
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DOI：
10.1186/1471-2121-8-52
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发表时间：
2007-12-19
期刊：
影响因子：
--
通讯作者：
Hackam AS
中科院分区：
文献类型：
--
作者：
Nakamura RE;Hunter DD;Yi H;Brunken WJ;Hackam AS
Wnt信号通路是一种细胞通讯通路，在发育和疾病中发挥着关键作用。一类主要的 Wnt 信号调节因子是 Dickkopf (Dkk) 分泌糖蛋白家族。尽管 Dickkopf 1 (Dkk1) 和 Dickkopf 2 (Dkk2) 的生物学特性已得到充分表征，但有关相关 Dickkopf 3 (Dkk3) 蛋白在体内或细胞系中的功能知之甚少。我们最近证明，在视网膜变性小鼠模型中，Dkk3 转录本在光感受器死亡期间上调。在这项研究中，我们表征了 Dkk3 在 Wnt 信号传导和细胞死亡中的活性。 Dkk3 定位于发育中和成年小鼠视网膜中的米勒神经胶质细胞和视网膜神经节细胞。蛋白质印迹证实 Dkk3 是由培养的 Müller 胶质细胞分泌的。我们证明 Dkk3 在 Müller 胶质细胞和 HEK293 细胞中增强 Wnt 信号传导，但在 COS7 细胞中则不然，表明它是 Wnt 信号传导的细胞类型特异性调节剂。这种独特的 Dkk3 活性被 Dkk1 的共表达所阻断。此外，Dkk3 通过减少 caspase 激活并增加暴露于星形孢菌素和 H2O2 的 HEK293 细胞的活力而显示出促生存特性。相反，Dkk3 不能保护 COS7 细胞免于凋亡。这些数据表明，与其家族成员 Dkk1 相比，Dkk3 是 Wnt 信号传导的正调节因子。此外，Dkk3 通过降低 caspase 活性来防止细胞凋亡，这表明 Dkk3 可能在视网膜中发挥细胞保护作用。
The Wnt signaling pathway is a cellular communication pathway that plays critical roles in development and disease. A major class of Wnt signaling regulators is the Dickkopf (Dkk) family of secreted glycoproteins. Although the biological properties of Dickkopf 1 (Dkk1) and Dickkopf 2 (Dkk2) are well characterized, little is known about the function of the related Dickkopf 3 (Dkk3) protein in vivo or in cell lines. We recently demonstrated that Dkk3 transcripts are upregulated during photoreceptor death in a mouse model of retinal degeneration. In this study, we characterized the activity of Dkk3 in Wnt signaling and cell death. Dkk3 was localized to Müller glia and retinal ganglion cells in developing and adult mouse retina. Western blotting confirmed that Dkk3 is secreted from Müller glia cells in culture. We demonstrated that Dkk3 potentiated Wnt signaling in Müller glia and HEK293 cells but not in COS7 cells, indicating that it is a cell-type specific regulator of Wnt signaling. This unique Dkk3 activity was blocked by co-expression of Dkk1. Additionally, Dkk3 displayed pro-survival properties by decreasing caspase activation and increasing viability in HEK293 cells exposed to staurosporine and H2O2. In contrast, Dkk3 did not protect COS7 cells from apoptosis. These data demonstrate that Dkk3 is a positive regulator of Wnt signaling, in contrast to its family member Dkk1. Furthermore, Dkk3 protects against apoptosis by reducing caspase activity, suggesting that Dkk3 may play a cytoprotective role in the retina.
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