Control factors of extravillious trophoblast differentiation

Physiological invasion of human placental trophoblast into uterine tissues of the pregnant mother is crucial for embryonic development but the molecular processes involved remain largely obscure. 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 wellbeing of the mother. Invasive differentiation of the trophoblast represents a physiological process sharing several features with the fibroblastoid conversion of neoplastic epithelial cells which occurs during local invasion and metastasis of carcinoma cells. Here, we propose to utilize different molecular techniques and trophoblast cell models to study regulatory factors and signalling cascades which we already identified by genome-wide mRNA expression profiling of invasive trophoblasts. In detail, signal transduction pathways critical for tumorigenesis such as Wnt-ß-catenin signalling and its downstream effectors, the transcriptional regulators LEF-1/TCF, will be investigated. In addition, novel techniques such as RNA interference will be utilised to delineate the role of putative key regulatory transcription factors of trophoblast invasion. The project will give insights into the critical steps of trophoblast cell invasion, thus providing the basis to better understand pregnancy-related diseases.

Physiological invasion of human placental trophoblast into uterine tissues of the pregnant mother is crucial for embryonic development but the molecular processes involved remain largely obscure. 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 wellbeing of the mother. Invasive differentiation of the trophoblast represents a physiological process sharing several features with the fibroblastoid conversion of neoplastic epithelial cells which occurs during local invasion and metastasis of carcinoma cells. Here, we propose to utilize different molecular techniques and trophoblast cell models to study regulatory factors and signalling cascades which we already identified by genome-wide mRNA expression profiling of invasive trophoblasts. In detail, signal transduction pathways critical for tumorigenesis such as Wnt-ß-catenin signalling and its downstream effectors, the transcriptional regulators LEF-1/TCF, will be investigated. In addition, novel techniques such as RNA interference will be utilised to delineate the role of putative key regulatory transcription factors of trophoblast invasion. The project will give insights into the critical steps of trophoblast cell invasion, thus providing the basis to better understand pregnancy-related diseases.