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General Comment |
Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Wang S et al. (2020) Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders. This gene is an ovarian endothelial cells //////////////////
NCBI Summary:
This gene encodes a classical cadherin of the cadherin superfamily. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion molecule is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Functioning as a classical cadherin by imparting to cells the ability to adhere in a homophilic manner, this protein plays a role in endothelial adherens junction assembly and maintenance. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. [provided by RefSeq, Nov 2015]
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Oocyte-derived E-cadherin acts as a multiple functional factor maintaining the primordial follicle pool in mice. Yan H et al. (2019) In mammals, female fecundity is determined by the size of the primordial follicle (PF) pool, which is established during the perinatal period. As a non-renewable resource, the preservation of dormant PFs is crucial for sustaining female reproduction throughout life. Although studies have revealed that several oocyte-derived functional genes and pathways, such as newborn ovary homeobox (NOBOX) and 3-phosphoinositide-dependent protein kinase-1, participate in maintaining the PF pool, our understanding of the underlying molecular mechanisms is still incomplete. Here, we demonstrate that E-cadherin (E-cad) plays a crucial role in the maintenance of PFs in mice. E-cad is specifically localized to the cytomembrane of oocytes in PFs. Knockdown of E-cad in neonatal ovaries resulted in significant PF loss owing to oocyte apoptosis. In addition, the expression pattern of NOBOX is similar to that of E-cad. Knockdown of E-cad resulted in a decreased NOBOX level, whereas overexpression of Nobox partially rescued the follicle loss induced by silencing E-cad. Furthermore, E-cad governed NOBOX expression by regulating the shuttle protein, β-catenin, which acts as a transcriptional co-activator. Notably, E-cad, which is a transmembrane protein expressed in the oocytes, was also responsible for maintaining the PF structure by facilitating cell-cell adhesive contacts with surrounding pregranulosa cells. In conclusion, E-cad in oocytes of PFs plays an indispensable role in the maintenance of the PF pool by facilitating follicular structural stability and regulating NOBOX expression. These findings shed light on the physiology of sustaining female reproduction.//////////////////
INHIBITION OF THE VASCULAR ENDOTHELIAL CELL SPECIFIC ADHESION MOLECULE VE-CADHERIN BLOCKS GONADOTROPIN-DEPENDENT FOLLICULOGENESIS AND CORPUS LUTEUM FORMATION AND ANGIOGENESIS Nakhuda GS, et al .
While it has been previously demonstrated that administration of anti-VEGFR-2 antibodies to hypophysectomized(Hx) mice during gonadotropin-stimulated folliculogenesis and luteogenesis inhibits angiogenesis in the developing follicle and corpus luteum(CL), it is unclear which of the many components of VEGF inhibition are important for the inhibitory effects on ovarian angiogenesis. To examine if ovarian angiogenesis can be more specifically targeted, we administered an antibody to VE-cadherin (VE-C), an interendothelial adhesion molecule, to Hx mice during gonadotropin stimulation. In tumor models, in vivo and in vitro assays, the anti-VE-C antibody, E4G10, has been shown to specifically inhibit angiogenesis, but VE-C has yet to be inhibited in the context of ovarian angiogenesis. In addition to studying the effect on neovascularization in the follicular and luteal phases, we also examined the effect of E4G10 on established vessels of the CL of pregnancy. The results demonstrate that E4G10 specifically blocks neovascularization in the follicular and luteal phases, causing an inhibition of preovulatory follicle and CL development, a decrease in the vascular area, and an inhibition of function demonstrated by reduced hormone levels. However, when administered during pregnancy, unlike anti-VEGFR-2 antibody, E4G10 is unable to cause disruption of the established vessels of the mature CL. This data demonstrates that E4G10 causes a specific inhibition of neovascularization in the ovary without destabilizing preexisting vasculature.
//////////VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs. Sidibe A 2014 et al.
In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 months old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross-section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (WT: 11.50.3, n=78; VE-Y685F: 12.480.3, n=65; p =0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or VEGF-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary permeability. Furthermore, this knock-in mouse model is of potential interest for further studies of diseases that are associated with abnormal vascular permeability.
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Prolactin independent rescue of mouse corpus luteum life span: identification of prolactin and luteinizing hormone target genes. Bachelot A et al. The corpus luteum (CL) plays a central role in the maintenance of pregnancy in rodents, mainly by secreting progesterone. Female mice lacking PRL receptor (R) are sterile due to a failure of embryo implantation which is a consequence of decreased LH receptor expression in the CL and inadequate levels of progesterone. We attempted to treat PRLR-/- females with hCG, and showed a de novo expression of LHR mRNA in the corpora lutea. Binding analysis confirmed that the LHR in hCG treated PRLR-/- animals was functional. This was accompanied with increased expression of steroidogenic enzymes involved in progesterone synthesis. Despite these effects, no embryo implantation was observed, due to high expression of 20-hydroxysteroid dehydrogenase. To better appreciate the molecular mechanisms underlying maintenance of the corpus luteum, a series of mRNA expression profiling experiments was performed on isolated corpora lutea of PRLR-/- and hCG-treated PRLR-/- mice. This approach revealed several novel candidate genes with potentially pivotal roles in ovarian function, among them, p27, VE-cadherin, Pten and sFRP-4, a member of the Wnt/frizzled family. This study showed the differential role of PRL and LH in corpus luteum function and identified new targets of these hormones in luteal cells. Key words: prolactin receptor, corpus luteum, LH receptor.
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