Y-Box Binding Protein 1 Expression in Trophoblast Cells Promotes Fetal and Placental Development

Abstract

Y-box binding protein 1 (YB-1) is pivotal for the regulation of cancerogenesis and inflammation. However, its involvement in pregnancy processes such as fetal and placental development remains to be elucidated. We studied Ybx1 (YB-1)+/− heterozygous intercrossings and compared them to YB-1+/+ wild-type (WT) combinations. Additionally, we generated trophoblast-specific YB-1-deficient mice by pairing FVB Cyp19-Cre females to YB-1fl/fl males. YB-1fl/fl-paired FVB WT females served as controls. Serial in vivo ultrasound measurements were performed to assess fetal and placental parameters. After sacrificing the females, implantation and abortion rates were recorded, spiral artery (SA) remodeling was analyzed and fetal and placental weights were determined. Compared to YB-1+/+ counterparts, YB-1+/− females showed reduced implantation areas at gestation day (GD)10, insufficiently remodeled SAs at GD12, increased placental diameter/thickness ratios at GD14 and reduced placental and fetal weights at GD14. Compared to WT, Cyp19-Cre females with YB-1-deficient placentas showed reduced implantation areas at GD8, 10 and 12; decreased placental areas and diameters at GD10 and 12; diminished placental thicknesses at GD12; as well as reduced placental weights at GD12 and 14. In conclusion, our data suggest haploinsufficiency of YB-1 resulting in disturbed fetal and placental development. Moreover, we provide the first evidence for the relevance of trophoblast-specific YB-1 for placentation.

YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits

“…During pregnancy, these processes are also crucial for the normal development of the placenta and changes in YB-1 expression might be involved in impaired placenta growth and/or functionality. We have recently shown that heterozygous YBX1 mice and mice with trophoblast-specific YBX1 deficiency display placental abnormalities with subsequent fetal growth retardation [20]. The present study demonstrates that pregnancy-associated disorders are associated with altered YB-1 concentrations in tissue and blood samples.…”

“…In YBX1-/-knockout embryos, the development advances usually up to embryonic day 10.5 (E10.5), and, afterwards, they exhibit severe growth retardation, neurological and pulmonary lesions, and are embryonically lethal by E18 [18,19], which indicates that YB-1 is necessary at late developmental stages. Recently, we characterized the effects of YB-1 deficiency on placenta development in vivo [20], where trophoblast-specific YB-1 deficient mice showed reduced implantation areas and negatively affected gross placental morphometry already at E10 [20]. This shows a direct involvement of YB-1 not only in placenta growth but also in implantation processes.…”

Compartmentalized regulation of NAD+ by Di (2-ethyl-hexyl) phthalate induces DNA damage in placental trophoblast

“…Our previous study has shown that maternal exposure to environmental pollutants DEHP during pregnancy induces fetal growth restriction by inhibiting the proliferation of placental cells through DNA damage [ 17 ]. Placental development defects are associated with fetal growth retardation, leading to adverse pregnancy outcomes and some diseases in adulthood of offsprings [ 39 , 40 ]. Therefore, it is very essential to understand the mechanism of DNA damage in placental cells treated by DEHP.…”

An old friend with a new face: YB-1 and its role in healthy pregnancy and pregnancy-associated complications

“…In addition to the fetal growth impairment, also the placenta showed certain functional and structural alterations in YB-1 deficiency. We have been able to show that IUGR might be a result of placenta insufficiency demonstrated by increased placental diameter/thickness ratio and weight at GD14 as well as inadequate SA remodeling in trophoblast-specific YB-1 deficient mice (Meyer et al, 2020). By overexpressing or downregulating YB-1 in two different trophoblast cell lines HTR8/SVneo and JEG3, we aimed to disclose the cellular mechanism underlying the placental dysfunction (Stojanovska et al, 2021).…”

“…Among the YB proteins, YB-1 seems to be developmentally most important: In comparison to the loss of YB-2 and YB-3, YB-1 is mostly embryonic lethal as demonstrated in YB-1 null mutant (YB1 −/− ) mice ( Lu et al, 2005 ; Uchiumi et al, 2006 ). However, the serious consequences of YB-1 deficiency become only evident after the first trimester, when a functional placenta is already established ( Meyer et al, 2020 ). This suggests that implantation and early decidualization are not dependent on YB-1 or that there are efficient compensatory mechanisms.…”