Notch信号通路在胚胎植入和蜕膜发育过程中的作用机制研究

Embryo implantation and decidua development are two determinants for successful pregnancy. The interactions between uterus and blastocyst during implantation share many features with trophectoderm-epithelial-mesenchymal interactions during embryogenesis, which involves conserved signaling pathways. Notch signaling pathway is highly conserved in evolution; it functions in nearly every developmental process of tissues and organs through cell-cell communication of neighbor cells during embryogenesis. However, the potential role of Notch signaling in periipmlantation is still unexplored. To address how this signaling participate in regulating the process of implantation and decidualization, we will employ multiple uterine selective transgenic and knockout mouse models as well as human clinical endometrial samples, to accordingly investigate: (1) the spatiotemporal expression pattern of Notch receptors, ligands and core transcriptional factor Rbpj in the periimplantation uterus; (2) the physiological role of Notch signaling pathway during embryo implantation and decidualization; (3) the involvement of Notch receptors-ligands and Rbpj during the establishment of endometrial receptivity and decidual transformation in humans; (4) novel mechanisms of Notch signaling pathway governing embryo implantation. It is hoped that a better understanding on developmental aspects of embryo implantation will provide theoretical basis and shed light on new therapy strategies design for early pregnancy loss in humans.

胚胎植入和蜕膜发育是决定妊娠成功与否的关键环节。子宫和囊胚之间进行的有序对话本质上是滋养层上皮-子宫上皮-子宫基质细胞之间相互作用，其中涉及多种发育相关信号分子参与。Notch信号通路在进化上高度保守，通过相邻细胞之间的相互作用调节细胞功能，在几乎所有组织、器官的分化和发育过程中均发挥重要作用。然而时至今日，该信号通路在子宫围植入期的功能研究仍然空缺。本项目拟利用多种转基因、子宫特异性敲除小鼠模型，结合子宫基质细胞体外培养及人工诱导蜕膜化模型，按照发育时程，系统研究：（1）Notch信号通路在围植入期子宫中的动态表达模式；（2）Notch 信号通路在胚胎植入和蜕膜发育过程中的作用机制；（3）Notch信号通路对人子宫内膜接受态及子宫内膜-蜕膜转化的调节机制；（4）Notch信号通路在胚泡着床中的新机制，以期从发育生物学角度进一步认识成功妊娠的分子基础，为胚泡着床失败等妊娠疾病提供理论基础。

胚胎植入和蜕膜发育是决定妊娠成功与否的关键环节。子宫和囊胚之间进行的有序对话本质上是滋养层上皮-子宫上皮-子宫基质细胞之间相互作用，其中涉及多种发育相关信号分子参与。Notch 信号通路在进化上高度保守，通过相邻细胞之间的相互作用调节细胞功能，在几乎所有组织、器官的分化和发育过程中均发挥重要作用。本项目主要利用多种转基因、子宫特异性敲除小鼠模型，结合体外生化分子实验发现子宫表达的Notch信号核心转录因子Rbpj对于雌性小鼠的生育是不可或缺的，在植入过程中Rbpj通过不依赖Notch受体的方式与雌激素受体ER互作调节其活性，进而影响着床小室的形成，在植入后蜕膜发育的过程中，Rbpj通过经典的Notch信号通路转录调控MMP等因子，进而影响蜕膜分化的过程。子宫中表达的Jag1受体对妊娠维持不是必须的，子宫特异敲除Jag1受体后雌性小鼠的胚胎植入、蜕膜发育和分娩等妊娠环节都没有明显异常。以上结果的取得证实了Notch经典信号在围植入期的重要生理作用，同时也提示作为一个配体和受体有多个成员的信号通路，体内生物学功能的发挥过程中往往存在代偿作用，需要更进一步通过更多模型来深入研究。