Critical Regulators of trophoblast invasion

Physiological invasion of human placental trophoblast into maternal uterine tissues is pivotal for embryonic development but the molecular processes involved remain largely unclear. Whereas shallow invasion is linked to the pathogenesis of the maternal hypertensive disorder preeclampsia and to fetal growth retardation, excessive proliferation and invasion occurs in mole gestations and choriocarcinomas suggesting that accurate control of the process is essential for embryonic survival and successful pregnancy. Invasive differentiation of the trophoblast represents a physiological process sharing several features with epithelial-mesenchymal transition (EMT), playing a role during local invasion and metastasis of neoplastic epithelialumour cells. In invasive trophoblasts E-cadherin becomes transiently downregulated, but the mechanism still remains obscure. Since invasive trophoblast exhibit epithelial but also mesenchymal features, they might undergo a partial EMT using the same critical factors that are required for tumorigenesis. Therefore, we here propose to utilize different molecular techniques and trophoblast cell models to study critical regulators of trophoblast differentiation and invasion which we already identified by genome-wide mRNA expression profiling of invasive trophoblasts. In detail, transcription factors Snail, Slug, SIP1, and Twist expression and function in invasive trophoblast differentiation will be investigated as they have been shown to play a key role in governing EMT by downregulation of E-cadherin expression. Novel techniques such as shRNAmir-mediated gene knock-down will be utilised to delineate the role of putative key regulatory transcription factors in trophoblast invasion. Furthermore the crosstalk between signalling pathways critical for invasive behaviour (cell adhesion, signal transduction, transcriptional regulation) involving Wnt/?- catenin signalling and its downstream effectors will be elucidated. This particular Hertha Firnberg Program will give insights into the critical steps of trophoblast cell invasion, thus providing the basis to better understand pregnancy-related diseases.