Tang Chao, Wang Jirong, Yao Minli, Ji Xing, Shi Wei, Xu Chengyun, Zeng Ling-Hui, Wu Ximei
Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Rd., Hangzhou, 310058, China.
National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China.
Cell Regen. 2023 Feb 1;12(1):3. doi: 10.1186/s13619-022-00151-6.
The overlapping roles of Hippo and Hedgehog signaling in biological functions and diseases prompt us to investigate their potential interactions. Activation of Hippo signaling enhances the transcriptional output of Hedgehog signaling, and the role of Hippo signaling in regulating Hedgehog signaling relies on the Hippo pathway key effector, Taz. Interestingly, Taz exhibits a gradient expression across the posterior-to-anterior of limb bud mesoderms, similar to Sonic hedgehog (Shh). Importantly, Taz drives PKA to phosphorylate Gli3, resulting in the Gli3 processing into its repressor and attenuation of Hedgehog signaling in the Shh-independent manner. Specifically, Taz deletion in mouse embryonic limb bud mesenchyme not only enhances the Hedgehog signaling but partially restores the phenotypes from Shh deletion in causing severe defects of anteroposterior patterning and digit number and identity. Together, these results uncover Taz-dependent Gli3 processing as a hitherto uncharacterized mechanism controlling Hedgehog signaling, highlighting its cross-regulation by Hippo signaling.
Hippo信号通路和刺猬信号通路在生物学功能和疾病中的重叠作用促使我们研究它们之间潜在的相互作用。Hippo信号通路的激活增强了刺猬信号通路的转录输出，并且Hippo信号通路在调节刺猬信号通路中的作用依赖于Hippo通路的关键效应因子Taz。有趣的是，Taz在肢体芽中胚层的后到前呈现梯度表达，类似于音猬因子（Shh）。重要的是，Taz促使蛋白激酶A（PKA）磷酸化Gli3，导致Gli3加工成其阻遏物并以不依赖Shh的方式减弱刺猬信号通路。具体而言，小鼠胚胎肢体芽间充质中Taz的缺失不仅增强了刺猬信号通路，还部分恢复了因Shh缺失导致的前后模式、指（趾）数量和特征严重缺陷的表型。总之，这些结果揭示了Taz依赖的Gli3加工是一种迄今未被描述的控制刺猬信号通路的机制，突出了其受Hippo信号通路的交叉调控。
