Influence of the TRPV6 ion channel on calcium-dependent processes in the female reproductive tract and the fetal yolk sac

• Applicants: Dr.-Ing. Claudia Fecher-Trost; Dr. Petra Weißgerber
• Subject Area: Pharmacology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445684568

The two closely related members of the TRPV family - TRPV6 and TRPV5 - selectively channel calcium ions and are inactivated by an increase in intracellular calcium. The Trpv6 gene is mainly expressed in placenta, exocrine glands and epididymal epithelia. In the lumen of the epididymis, TRPV6 is essential for Ca2+ homeostasis during sperm maturation; male mice lacking functional TRPV6 channels show severe impaired fertility (Weissgerber et al., 2011, 2012). In the placenta, TRPV6 is important for the calcium supply of the embryo. Using genetically engineered TRPV6 mouse models, we were able to show that growth and bone development in Trpv6-deficient embryos is altered as a result of reduced calcium supply during pregnancy (Fecher-Trost et al., 2019). The lack of functional TRPV6 channels in the mother leads to a reduced Ca2+ content in both the placenta and the embryo. In the placenta, TRPV6 is expressed in the labyrinth trophoblasts, which are in direct contact with maternal blood. Trpv6-deficient trophoblasts absorb significantly less calcium and show reduced crosslink with cells. However, embryo transfer experiments with embryos of different genotypes implanted in WT and Trpv6-deficient mothers show that both the maternal and fetal parts of the placenta contribute to embryonic development and calcium accumulation in the bones (Fecher-Trost et al. 2019). In addition, the high level of TRPV6 expression in the maternal decidua resulting from endometrial transformation as well as in the yolk sac suggests that the phenotype of the Trpv6-deficient embryos is not due solely to the absence of the trophoblast TRPV6 channel, but additionally could also depend on the function of the canal in the endometrium and / or the yolk sac. On the basis of these findings, we now ask ourselves which cell type, together with the trophoblasts, is responsible for the described TRPV6 phenotype? Therefore, we want to characterize the expression and function of the TRPV6 channel i) in the yolk sac and ii) in the endometrium or in the decidua before and during pregnancy and, for the first time, the role of TRPV6 during the cyclic processes responsible for the development of the decidua. In particular, the hormone-dependent changes of the endometrium within the normal menstrual cycle, the physiological function of TRPV6 in the biogenesis of the decidua as a prerequisite for the implantation of the blastocyst and the maintenance of pregnancy in vivo should be characterized as central points. We are particularly interested in the impact of a lack of TRPV6 on female fertility (fecundity).

• DFG Programme: Research Grants