CCN3 (NOV): Key regulator promoting cell cycle exit and migration of trophoblast cells into the maternal compartment

适当的胎盘形成依赖于妊娠早期EVT细胞的增殖能力，然后在脱离细胞周期后侵入母体组织。在这个高度协调的程序的变化可能会导致妊娠疾病先兆子痫的特点是滋养层低侵袭和缺陷的血管重塑。我们已经表明，基质细胞蛋白CCN 3有助于调节开关从增殖的滋养细胞的细胞柱的非增殖表型侵入蜕膜和螺旋动脉在胎盘发育过程中，通过引起G 0/G1细胞周期阻滞以及增强迁移特性。细胞周期停滞伴随着活化的Notch 1及其靶基因p21的表达增加。同时，CCN 3通过整合素激活FAK和Akt信号通路，增加滋养层细胞的迁移特性，我们希望更精确地研究CCN 3如何调控G 0/G1细胞周期阻滞以及如何同时触发迁移以实现成功的胎盘发育的详细分子机制。此外，我们想确定受损的信号级联CCN 3介导的增殖和/或迁移特性在早发性先兆子痫。

Appropriate placentation relies on the capacity of first trimester EVT cells to proliferate and then to invade into the maternal tissue after having escaped from the cell cycle. Changes in this highly coordinated programme could lead to the pregnancy disease preeclampsia characterized by trophoblast hypoinvasion and defective vascular remodeling.We have shown that the matricellular protein CCN3 contributes to the regulation of the switch from the proliferating trophoblast of the cell column to the non-proliferating phenotype invading the decidua and the spiral arteries during placental development by causing a G0/G1 cell cycle arrest as well as enhancing migration properties. The cell cycle arrest is accompanied by an increased expression of activated Notch1 and its target gene p21. At the same time CCN3 increases migration properties of trophoblast cells by an activation of FAK and Akt pathways via integrins.In this proposed study we want to investigate more precisely the detailed molecular mechanisms how CCN3 regulates the G0/G1 cell cycle arrest and how the migration can be triggered at the same time to fulfil a successful placental development. Moreover, we would like to identify impaired signaling cascades mediated by CCN3 for proliferation and / or migration properties in early-onset preeclampsia.