Wnt-Frizzled2信号调节小鼠胚胎植入和蜕膜发育的分子机制

Embryo implantation and decidualization are two critical events occurred in the uterus for the successful pregnancy, which are precisely under the control of many uterine molecules. Previous studies demonstrated that Wnt5a and Wnt4 protein had participated in regulating these two processes, while it remains elusive whether uterine Frizzled receptor mediates these two ligands in regulating implantation and decidualization through non-canonical Wnt signaling pathway. In the present project, we showed decidual reaction and embryonic development are disrupted by conditional knockout of uterine Frizzled2. We intend to further investigate whether uterine Frizzled2 receptor mediates Wnt5a and Wnt4 ligands, and the specific molecular mechanism of Wnt-Frizzled2 signaling pathway in regulating implantation and decidualization, attempting to comprehensively reveal the function of uterine non-canonical Wnt-Frizzled2 signaling during pregnancy establishment and maintenance, and provide theoretical basis for related pregnancy diseases.

胚胎植入和蜕膜发育是决定妊娠成功的两个关键环节，并受到子宫细胞内多种分子的精确调控。先前研究证实Wnt5a、Wnt4蛋白参与调节植入和蜕膜化，而其卷曲蛋白受体Frizzled是否介导两类配体并通过非经典Wnt信号通路发挥功能尚不清楚。申请人在前期研究中发现子宫条件性敲除Frizzled2影响蜕膜反应和胚胎发育。本项目拟进一步研究子宫Frizzled2分子是否介导Wnt5a和Wnt4配体，以及Wnt-Frizzled2信号影响胚胎植入和蜕膜化的分子调控机制，以期揭示非经典Wnt-Frizzled2通路对妊娠建立与维持的关键作用，为临床相关妊娠疾病提供理论依据。

胚胎植入和蜕膜发育是决定妊娠成功的两个关键环节。经典Wnt信号通路的相关分子在调节植入和蜕膜化过程中发挥重要功能，而非经典Wnt信号通路对此过程的调节机制有待深入研究。本项目筛选到非经典Wnt蛋白的受体卷曲蛋白受体2（Frizzled2，简称Fzd2）在围植入期子宫中高表达，并且人工诱导蜕膜化的子宫蜕膜细胞中Fzd2也高表达，因此我们建立了子宫细胞特异敲除Fzd2基因的条件性敲除小鼠模型（Fzd2f/f,Pgrcre/+，简称Fzd2d/d），发现子宫中缺失Fzd2影响植入和蜕膜发育，进而引起胚胎发育迟缓，并导致孕中期部分胚胎的吸收死亡。通过检测围植入期增殖、分化、凋亡、上皮间质转化等相关的重要分子或标志性分子，发现Fzd2影响非经典Wnt信号下游分子Rac1的表达。本项目通过探讨Fzd2的分子调节机制，为说明非经典Wnt-Fzd2信号参与植入和蜕膜发育调节提供了重要的理论支持。