RBPJ介导的信号通路对胎盘发育的调控机制研究

Placenta, forming the interface between the mother and fetus, is responsible for the exchanges of nutrients and gases between the maternal and fetal circulation and is essential for the survival and development of fetus. Any disturbance to placental development often results in placenta-related diseases. It has been reported that RBPJ contributes to the fusion of the chorion and allantois during the early stages of placental development. However, little is known regarding the mechanisms how RBPJ-mediated signaling controls placental growth and development. Our preliminary experiments showed that allantois-expressed RBPJ was essential for chorioallantoic fusion and branching morphogenesis. Also, we found that RBPJ was involved in the trophoblast differentiation derived in the ectoplacental cone. Employing conditional knockout mice models and the in vitro differentiation of trophoblast stem cells, the project aims to precisely elucidate the mechanism of RBPJ-mediated signaling pathway on chorioallantoic fusion and branching morphogenes, fetal vascular morphogenesis and the specification of trophoblast cells in order to further understand the molecular interaction networks that regulate placental development, providing the theoretical evidence for the prevention and treatment of placenta-related diseases.

胎盘形成了胎儿和母体之间的界面，是母体和胎儿之间进行营养和气体交换的必需器官，对胎儿的存活和发育起着至关重要的作用。胎盘异常经常会导致胎盘发育相关的妊娠疾病。已有研究发现RBPJ影响胎盘发育过程中尿囊绒毛膜融合，但对RBPJ调控胎盘发育的作用机制却知之甚少。我们的预实验结果显示尿囊表达的RBPJ对尿囊绒毛膜融合及分支的形态发生过程是必不可少的。同时，我们还发现RBPJ也影响外胎盘锥滋养层细胞的分化。因此，本课题拟在此基础上利用条件敲除小鼠模型和滋养层干细胞体外培养及分化模型进一步阐明RBPJ介导的信号通路对尿囊绒毛膜融合及分支的形态发生和胎盘血管发生的作用机理，同时也揭示RBPJ介导的信号对滋养层细胞分化的调控机制，以期进一步认识胎盘发育的分子调控网络，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。

胎盘负责母体与胎儿之间的营养和气体交换。已有研究表明，Rbpj是作为Notch信号传导的核心转录调控因子，对小鼠正常的胎盘发育是必需的。然而，Rbpj信号如何调控胎盘发育的分子机制尚不清楚。在这项研究中，我们发现全身性敲除Rbpj导致异常的尿囊绒毛膜形态发生，以及引起外胎盘锥滋养细胞的分化存在缺陷。使用尿囊或滋养细胞特异性敲除Rbpj的小鼠模型，结合四倍体补偿实验，我们证明了尿囊表达Rbpj对尿囊绒毛膜融合（chorioallantoic fusion）和胎盘分支（braching）形态发生至关重要。进一步的研究表明，尿囊表达的Rbpj以Notch依赖的方式调控Vcam1基因表达，进而调节尿囊绒毛膜融合。同时，我们还揭示了外胎盘锥 (ectoplacental cone) 滋养细胞表达Rbpj能够增强Mash2的转录因子功能，进而能够促进Tpbpα阳性的滋养细胞特化，其调控分化的滋养细胞亚型在胎盘发育后期负责血管内浸润。总而言之，我们的研究进一步阐明了调控胎盘发育和功能的分子网络，突出了Rbpj信号的时空协调表达对于正常胎盘形态发生的必要性。我们的研究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。