The role of tight junction proteins in ovarian follicular development and ovarian cancer. Zhang L et al. (2018) Tight junctions (TJ) are protein structures that control the transport of water, ions and macromolecules across cell layers. Functions of the transmembrane TJ protein, occludin (OCLN), and the cytoplasmic TJ proteins, tight junction protein 1 (TJP1; also known as zona occludens protein-1), cingulin (CGN), and claudins (CLDN) are reviewed, and current evidence of their role in the ovarian function is reviewed. Abundance of OCLN, CLDNs, and TJP1 mRNA changed during follicular growth. In vitro treatment with various growth factors known to affect ovarian folliculogenesis indicated that CGN, OCLN and TJP1 are hormonally regulated. The summarized studies indicate that expression of TJ proteins (i.e., OCLN, CLDN, TJP1 and CGN) changes with follicle size in a variety of vertebrate species but whether these changes in TJ proteins are increased or decreased depends on species and cell type. Evidence indicates that autocrine, paracrine and endocrine regulators, such as fibroblast growth factor-9, epidermal growth factor, androgens, tumor necrosis factor-α and glucocorticoids may modulate these TJ proteins. Additional evidence presented indicates that TJ proteins may be involved in ovarian cancer development in addition to normal follicular and luteal development. A model is proposed suggesting that hormonal downregulation of TJ proteins during ovarian follicular development could reduce barrier function (i.e., selective permeability of molecules between theca and granulosa cells) and allow for an increase in the volume of follicular fluid as well as allow additional serum factors into the follicle that may directly impact granulosa cell functions.//////////////////
NCBI Summary:
This gene encodes an integral membrane protein which is located at tight junctions. This protein may be involved in the formation and maintenance of the tight junction. The possibility of several alternatively spliced products has been suggested but the full nature of these products has not been described. [provided by RefSeq]
General function
Cell adhesion molecule
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Early embryo development
Comment
Evidence that gene expression of ovarian follicular tight junction proteins is regulated in vivo and in vitro in cattle. Zhang L et al. (2017) Tight junctions (TJ) are common paracellular sealing structures that control the transport of water, ions, and macromolecules across cell layers. Because the role of TJ in bovine follicular development is unknown, we investigated the developmental and hormonal regulation of the transmembrane TJ protein, occludin (OCLN), and the cytoplasmic TJ proteins, TJ protein 1 (TJP1) and cingulin (CGN) in bovine granulosa cells (GC) and theca cells (TC). For this purpose, bovine GC and TC were isolated from large (>8 mm) and/or small (1 to 5 mm) follicles and either extracted for real-time PCR (qPCR) or cultured in vitro. The abundances of both and mRNA were greater ( < 0.05) in TC than GC, whereas the mRNA abundance was greater ( < 0.05) in GC than TC. The abundance of mRNA in both GC and TC was greater ( < 0.05) in small follicles compared with large follicles, whereas the GC of large follicles had less ( < 0.05) mRNA abundance than the GC of small follicles. The abundance of mRNA in GC or TC did not differ ( > 0.10) among follicle sizes. In vitro treatment with various growth factors known to affect ovarian folliculogenesis indicated that , , and were hormonally regulated. Fibroblast growth factor 9 (FGF9) decreased ( < 0.05) the and mRNA abundances. Tumor necrosis factor α (TNFα) and vascular endothelial growth factor A (VEGFA) increased ( < 0.05) the mRNA abundance but decreased ( < 0.05) the mRNA abundance. Dexamethasone (DEX) increased ( < 0.05) and mRNA abundances. Epidermal growth factor (EGF) decreased ( < 0.05) and dihydrotestosterone (DHT) increased ( < 0.05) the abundances of , , and mRNA. We propose that the downregulation of OCLN and other TJ proteins during follicular development could reduce barrier function, thereby participating in increasing follicle size by allowing for an increase in the volume of follicular fluid as well as by allowing additional serum factors into the follicular fluid that potentially may directly impact GC functions. The results of the current study indicate the following in cattle: 1) gene expression of TJ proteins (i.e., , , and ) differs between GC and TC and changes with follicle size, and 2) autocrine, paracrine, and endocrine regulators, such as FGF9, EGF, DHT, TNFα, and glucocorticoids, modulate , , and mRNA abundance in TC in vitro.//////////////////
Expression regulated by
FSH, Growth Factors/ cytokines
Comment
Regulation of tight junction proteins occludin and claudin 5 in the primate ovary during the ovulatory cycle and after inhibition of vascular endothelial growth factor. Rodewald M et al. Ovarian follicular and corpus luteum development, including angiogenesis, are characterized by cell-cell rearrangements that may require dynamic changes in cell-cell adhesion. The present study investigates the expression of tight junction proteins occludin and claudin 5 during follicular and luteal development in the primate ovary and after inhibition of vascular endothelial growth factor (VEGF) by VEGF trap treatment. Occludin was localized to the plasma membrane of granulosa cells. During follicular development occludin staining decreased significantly (P < 0.05) and disappeared completely by the ovulatory stage. After inhibition of VEGF, occludin staining was significantly (P < 0.05) higher in the granulosa of secondary and tertiary follicles compared with controls. Claudin 5 was exclusively localized to the theca vasculature. A significant (P < 0.05) increase in staining was detected from the pre-antral to the antral and ovulatory stage. However, dual staining with CD31 revealed that within the theca endothelium the amount of claudin 5 remained constant during follicular development. Treatment with VEGF trap throughout the follicular phase revealed a lack of claudin 5 staining in the theca interna but no difference was observed in the remaining theca externa vasculature. In the corpus luteum, claudin 5 was also localized in the vasculature. Treatment with VEGF trap in the mid-luteal phase resulted in a significant increase in staining (P < 0.05). These results led us to hypothesize that tight junctions are involved in regulation of follicular growth, antrum transition and follicular angiogenesis which is compromised by VEGF inhibition. VEGF may influence luteal vascular permeability by regulation of the endothelial specific tight junction protein claudin 5.
Ovarian localization
Oocyte, Granulosa, Theca
Comment
Expression of ZO-1 and occludin at mRNA and protein level during preimplantation development of the pig parthenogenetic diploids. Xu S et al. SummaryExpression of mRNAs and proteins of ZO-1 and occludin was analyzed in pig oocytes and parthenogenetic diploid embryos during preimplantation development using real-time RT-PCR, western blotting and immunocytochemistry. All germinal vesicle (GV) and metaphase (M)II oocytes and preimplantation embryos expressed mRNAs and proteins of ZO-1 and occludin. mRNA levels of both ZO-1 and occludin decreased significantly from GV to MII, but increased at the 2-cell stage followed by temporal decrease during the early and late 4-cell stages. Then, both mRNAs increased after compaction. Relative concentration of zo1a- was highest in 2-cell embryos, while zo1a+ was expressed from the morula stage. Occludin expression greatly increased after the morula stage and was highest in expanded blastocysts. Western blotting analysis showed constant expression of ZO-1a- throughout preimplantation development and limited translation of ZO-1a+ from the blastocysts, and species-specific expression pattern of occludin. Immunocytochemistry analysis revealed homogeneous distribution of ZO-1 and occludin in the cytoplasm with moderately strong fluorescence in the vicinity of the contact region between blastomeres, around the nuclei in the 2-cell to late 4-cell embryos, and clear network localization along the cell-boundary region in embryos after the morula stage. Present results show that major TJ proteins, ZO-1 and occludin are expressed in oocytes and preimplantation embryos, and that ZO-1a+ is transcribed by zygotic gene activation and translated from early blastocysts with prominent increase of occludin at the blastocyst stage.
Activin a and follicle-stimulating hormone control tight junctions in avian granulosa cells by regulating occludin expression.
Within the avian ovarian follicle, the oocyte is surrounded by a monolayer of granulosa cells, which exhibit pronounced epithelial properties. Here Schuster MK, et al demonstrate the presence of the major tight junction protein occludin in granulosa cells. As shown by immunohistochemistry, occludin localizes to the oocyte-facing granulosa cell surface. Occludin and thus tight junctions are dynamically regulated in a developmental stage-specific manner. Small white follicles, which have not yet started yellow yolk incorporation, show pronounced occludin expression in vitro and in vivo. By contrast, yellow yolk-incorporating small yellow follicles exhibit much lower levels of occludin, and hierarchical, preovulatory follicles are virtually devoid of this essential tight junction component. Using a primary granulosa cell culture system, we demonstrate that concerted action of two well-established ovarian growth regulators, follicle-stimulating hormone and activin A, leads to strong induction of occludin expression in vitro. We suggest that the stage-dependent decrease in the granulosa cell growth factor responsiveness triggers the disruption of tight junctions, enabling rapid and high capacity transport of macromolecules into the oocyte through a paracellular pathway. Such a high-capacity transport for yolk components may represent a crucial prerequisite for rapid oocyte growth once follicles have entered the follicular hierarchy.