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

合适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。这种高度协调的程序的变化可能导致以滋养层低侵袭和血管重建缺陷为特征的妊娠期疾病先兆子痫。我们已经证明，在胎盘发育过程中，基质细胞蛋白CCN3通过引起G0/G1细胞周期停滞和增强迁移特性，有助于调节胎盘发育过程中从细胞柱的增殖滋养细胞到侵入蜕膜和螺旋动脉的非增殖表型的转换。伴随着细胞周期停滞的是激活的Notch1及其靶基因p21的表达增加。同时，CCN3通过整合素激活FAK和Akt通路，增加滋养层细胞的迁移特性。在这项拟议的研究中，我们希望更准确地研究CCN3如何调节G0/G1细胞周期停滞的详细分子机制，以及如何同时触发迁移以实现胎盘的成功发育。此外，我们希望确定早发性子痫前期中CCN3介导的增殖和/或迁移特性受损的信号级联反应。

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.