Abstract
Calcium-selective transient receptor potential Vanilloid 6 (TRPV6) channels are expressed in fetal labyrinth trophoblasts as part of the feto–maternal barrier, necessary for sufficient calcium supply, embryo growth, and bone development during pregnancy. Recently, we have shown a less- compact labyrinth morphology of Trpv6-deficient placentae, and reduced Ca2+ uptake of primary trophoblasts upon functional deletion of TRPV6. Trpv6-/- trophoblasts show a distinct calcium-dependent phenotype. Deep proteomic profiling of wt and Trpv6-/- primary trophoblasts using label-free quantitative mass spectrometry leads to the identification of 2778 proteins. Among those, a group of proteases, including high-temperature requirement A serine peptidase 1 (HTRA1) and different granzymes are more abundantly expressed in Trpv6-/- trophoblast lysates, whereas the extracellular matrix protein fibronectin and the fibronectin-domain-containing protein 3A (FND3A) were markedly reduced. Trpv6-/- placenta lysates contain a higher intrinsic proteolytic activity increasing fibronectin degradation. Our results show that the extracellular matrix formation of the placental labyrinth depends on TRPV6; its deletion in trophoblasts correlates with the increased expression of proteases controlling the extracellular matrix in the labyrinth during pregnancy.
Highlights
Ca2+ transport through the transient receptor potential vanilloid 6 (TRPV6) channel across the feto–maternal barrier plays a pivotal role in embryonic development and bone development [1]
Our results show that the extracellular matrix formation of the placental labyrinth depends on transient receptor potential Vanilloid 6 (TRPV6); its deletion in trophoblasts correlates with the increased expression of proteases controlling the extracellular matrix in the labyrinth during pregnancy
The proteomic profiling of wt and Trpv6-/- placental trophoblasts led to the identification of 2778 proteins, with 35 proteins being significantly-more abundant in Trpv6-deficient trophoblasts
Summary
Ca2+ transport through the transient receptor potential vanilloid 6 (TRPV6) channel across the feto–maternal barrier plays a pivotal role in embryonic development and bone development [1]. The genotype of the maternal part of the placenta is responsible for the pronounced effect on the bone mineralization because the offspring of homozygous Trpv6-deficient females are much more affected than the offspring from heterozygous females [1] This is consistent with case reports in humans, where mutations in the Trpv gene lead to the hereditary human disease transient neonatal hyperparathyroidism (HRPTTN, OMIM #618188) associated with skeletal abnormalities, dysplasia, and elevated neonatal parathyroid hormone levels [14,15,16,17,18]. Key initial observations in the placenta of pregnant mice were that both the deletion of the Trpv gene (Trpv6-/-) and the functional inactivation of the TRPV6-ion-conducting pore by a point mutation (Trpv6mt/mt) led to morphological changes of the placental labyrinth, a reduction of Ca2+ accumulation in the embryo up to E14.5, and a reduced Ca2+ uptake by Trpv6-deficient trophoblasts isolated from these animals
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