Hippo信号调控Hedgehog信号的机制和意义研究

The cross-talk between a variety of signals is essential for cell behavior and cell functions that are well-coordinated events regulated by multiple cellular signals. Giving the fact that there are broad interaction between the Wnt and Hippo signals, we assume that there is also an interaction between the Hippo signaling and Hedgehog signaling that functions as the upstream of Wnt signaling. Our premier data have shown that TAZ, a key co-factor of Hippo signaling, negatively regulates Hh signaling possibly through promoting the conversion of full-length Gli3 (Gli3F) to its repressor form (Gli3R), and that knockout of TAZ partially rescues the digital defects resulted from Sonic hedgehog knockout. Based on these observation, this project will focuses on the detailed roles and mechanisms of TAZ in regulation of Hh signaling and the development of digitals of limb bud. This study will provide with new mechanism governing Hh signaling, and will further strengthen the physiological effects of Hippo signaling in the development of limb buds.

细胞行为和功能的调控是多个信号协调的结果，因此，细胞信号之间的cross-talk也广泛存在。已有研究表明Wnt和Hippo信号间存在广泛的相互作用，那么，作为Wnt信号上游的Hedgehog(Hh)信号是否也与Hippo信号之间存在互作？我们探索性的研究结果表明：Hippo信号关键因子TAZ可能通过促进Hh信号关键转录因子Gli3转化成截短形式而抑制Hh信号；而且，肢芽中敲除TAZ由于减少Gli3截短形式相对激活Hh信号，从而挽救了sonic hedgehog敲除所导致的手指发育缺陷。以上述结果为基础，本项目拟利用体外细胞模型和基因敲除小鼠模型，进一步研究Hippo信号调控Hh信号的具体效应和分子机制，以及可能的在肢芽早期发育中的重要生理意义。通过本研究不仅为Hh信号提供新的调控机制，而且进一步充实Hippo信号的生理效应；也将为器官发育、肿瘤形成、组织稳态维持的过程提供新的理论。