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

TRPV家族的两个密切相关的成员-TRPV6和TRPV5-选择性地通道钙离子，并被细胞内钙的增加所灭活。TRPV6基因主要在胎盘、外分泌腺和附睾上皮细胞中表达。在附睾腔中，TRPV6对于精子成熟过程中的钙稳态是必不可少的；缺乏功能TRPV6通道的雄性小鼠表现出严重的生育能力受损(Weissgerber等，2011,2012)。在胎盘中，TRPV6对胚胎的钙供应很重要。使用转基因的TRPV6小鼠模型，我们能够证明TRPV6缺陷胚胎的生长和骨骼发育因怀孕期间钙供应减少而改变(Fecher-Trost等人，2019年)。母亲体内缺乏功能强大的TRPV6通道，导致胎盘和胚胎中的钙含量降低。在胎盘中，TRPV6表达于与母体血液直接接触的迷路滋养层细胞。缺乏TRPV6的滋养层细胞吸收的钙显著减少，与细胞的交联性降低。然而，将不同基因类型的胚胎植入WT和TRPV6缺陷母亲体内的胚胎移植实验表明，胎盘的母体和胎儿部分都有助于胚胎发育和骨骼中钙的积累(Fecher-Trost等人)。2019年)。此外，TRPV6在子宫内膜转化的母体蜕膜和卵黄囊中的高水平表达表明，TRPV6缺陷胚胎的表型不仅仅是由于滋养层TRPV6通道的缺失，还可能取决于子宫内膜和/或卵黄囊中通道的功能。在这些发现的基础上，我们现在问自己，是哪种细胞类型与滋养层细胞一起，导致了所描述的TRPV6表型？因此，我们想要研究TRPV6通道I)在卵黄囊和II)在子宫内膜或蜕膜中的表达和功能，以及第一次研究TRPV6在蜕膜发育的周期过程中的作用。特别是，正常月经周期内子宫内膜的激素依赖性变化，作为胚泡着床和体内妊娠维持的先决条件的TRPV6在蜕膜生物发生中的生理功能应该被描述为中心点。我们特别感兴趣的是缺乏TRPV6对女性生育力(繁殖力)的影响。

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).