Wnt-Frizzled5信号通路调控胎盘迷路层发育的机制研究

The labyrinth of placenta is essential for the survival and development of the fetus. And any disturbance to the development of the labyrinth would lead to pregnancy-related diseases, even the failure of the pregnancy. Our previous work demonstrated that canonical Wnt2-Frizzled5 signaling pathway regulated chorionic branching morphogenesis and trophoblast syncytializaiton during labyrinth development through forming positive feedback loop with Gcm1. Our preliminary data further showed that the chorionic branching occurring at the basal chorionic plate is an EMT-like process. And Frizzled5 deficiency derailed EMT-like dynamics and impaired the activation of the Rho GTPases. In the present project, employing placenta-specific mouse models and in vitro trophoblast cell lines, we will investigate the cell events occurring during chorionic branching and trophoblast syncytializaiton during the labyrinth development, uncover the the important role of Frizzled5-mediated noncanonical Wnt signaling during chorionic branching and trophoblast syncytializaiton and the interactions between noncanonical Wnt-Frizzled5 signaling and canonical Wnt signaling during these processes. Our project is to further clarify the molecular mechanism of placental labyrinth development, providing theoretical evidence for the prevention and treatment of placenta-related diseases.

胎盘迷路层对妊娠过程中胎儿的存活和发育至关重要，其发育异常会导致妊娠相关疾病，严重时可导致胎儿死亡。前期研究已证实经典Wnt2-Frizzled5信号通过与Gcm1形成正反馈回路调控胎盘迷路层发育中的绒毛膜分支和滋养层细胞合体化。预实验数据进一步显示迷路层发育过程中绒毛膜基部滋养层细胞发生EMT样变化，Frizzled5缺失导致EMT样变化的失败，Rho GTPases不能被激活，这提示我们Frizzled5可能通过非经典Wnt信号参与绒毛膜分支和滋养层细胞的合体化。本项目中，申请人拟利用胎盘特异性小鼠模型和滋养层细胞系模型系统研究绒毛膜分支和滋养层细胞合体化中的细胞学事件，揭示非经典Wnt-Frizzled5信号对绒毛膜分支和滋养层细胞合体化的调控作用及在此过程中与经典Wnt信号通路的互作，以期进一步认识胎盘迷路层发育的分子机制，为从源头上预防和治疗胎盘发育相关的妊娠疾病提供理论依据。

胎盘对胎儿在子宫内的发育和出生后乃至成年期的健康至关重要。胎盘发育的异常会引起妊娠相关疾病，甚至会导致妊娠失败和胎儿死亡。胎盘尿囊绒毛膜分支和滋养层细胞的合体化是形成母胎交换界面-迷路层的关键事件。在本项目中，我们利用胎盘特异性小鼠模型研究了Fzd5介导的非经典Wnt信号对胎盘尿囊绒毛膜分支和滋养层细胞合体化的调控机制。研究发现，1）绒毛膜基部的滋养层细胞的形态变化和增殖是分支发生的推动力；2）分支发生过程中绒毛膜基部的滋养层细胞发生EMT样的变化；3）Fzd5介导的Wnt/Rho GTPase信号通路可能通过YAP/TAZ调节绒毛膜分支过程中EMT样变化的发生。以上发现揭示了胎盘尿囊绒毛膜分支和滋养层细胞合体化的调控机制，为妊娠相关疾病的早期诊治和干预提供了新的思路。