Dissecting the participation of cold shock proteins in reproductive processes: relevance of trophoblast specific YB-1 expression for embryo development

• Applicant: Professorin Dr. Ana Claudia Zenclussen
• Subject Area: Reproductive Medicine, Urology ; Gynaecology and Obstetrics
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404991393

The detailed study of pregnancy-associated processes is of pivotal importance for the development of strategies to help reproductively challenged couples. Uterine adaptations to pregnancy are crucial for placentation, in particular for the remodeling of the spiral arteries, a process that implies the conversion of existent spiral arteries into thin-walled arteries with as an adaptation to the increasing blood volume. Suboptimal remodeling cause an inadequate supply of nutrients and/or exchange of gases and waste between the mother and fetus that can lead to pregnancy complications such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE). Not only do these changes danger pregnancy itself but also they greatly influence adult health later. Although research has significantly advanced in the last years, still much work is necessary to understand the cellular and molecular mechanisms underlying IUGR and/or PE. An accurate understanding of the basic mechanisms governing both, implantation and placentation is urgently needed. This application aims to understand the participation of cold shock proteins that, until now, have not been studied in the context of pregnancy. Our first experiments suggest a correlation of YB-1 transcript numbers with IUGR. In placental tissue from patients with IUGR fetuses, YB-1 mRNA was significantly decreased compared to controls. Thus, low YB-1 levels may be related with poor trophoblast physiology.YB-1 +/- females presented an increased number of IUGR feto-placental units compared to the controls at days 8, 10 and day 12 of pregnancy as analyzed by ultrasound. At day 12, placentas from heterozygote mating combinations presented histological abnormalities, such as disorganized area of spongiotrophoblasts and thin labyrinth. No homozygote fetuses were viable after day 12. We found that animals born to YB-1+/- mothers had thicker artery walls with narrower lumens, resulting in enhanced wall-to-lumen ratio. The fact that YB-1+/+ implantations from YB-1+/- mothers also had increased ratios suggests that the uterine environment may play a role in the development of SA. Reduced lumen in these animals means an insufficient blood supply to the fetus and thus, a reduced availability of nutrients and oxygen that can lead to growth restriction while in uterus. Hence, we hypothesize that YB-1 mediates relevant pregnancy-associated processes, including placentation and spiral artery remodeling. Trophoblast-specific YB-1 may have the capacity to regulate the finely orchestrated balance between invasion, proliferation, differentiation, apoptosis, and angiogenesis that is essential for the well-being of the fetus and its proper development. By combining elegant animal models and analysis of human tissue samples, we expect to unravel the participation of cold shock proteins in reproduction.

• DFG Programme: Research Grants