Eran Gershon

Gap junctions in the ovary: expression, localization and function.

Gap junctions that allow the direct communication between cytoplasmic compartments of neighboring cells are present in a variety of tissues and organs and play pivotal roles in a wide range of physiological processes. In the ovary, gap junctions consist mainly of connexin (Cx) 43 and Cx37, and their indispensable role in regulating folliculogenesis and oogenesis is well established. The ovarian Cx43 is regulated by gonadotropins at the transcriptional, translational and post-translational levels whereas the regulation of the ovarian Cx37 is yet unknown. In addition to their involvement in normal ovarian functions, gap junction proteins, particularly Cx43, seem to act as cancer suppressors. A summary of our present knowledge regarding gap junctional communication (GJC) and the ovarian gap junction proteins in normally developing ovaries and under pathological conditions is presented in this review.

Low expression of COX-2, reduced cumulus expansion, and impaired ovulation in SULT1E1-deficient mice

The SULTlEl‐encoded estrogen sulfo‐transferase (EST) catalyzes sulfation of estrogen, resulting in its inactivation. Reduced fertility observed in SULT1E1 knockout (KO) female mice has previously been attributed to the deleterious effect of chronic exposure to high levels of circulating estrogen on placental function. We herein suggest that, in addition to placental dysfunction, this phenotype demonstrates that an excess of estrogen impairs ovulation. The role of SULT1E1 in ovulation is suggested by the substantially low ovulatory response in hCG‐treated SULT1E1 KO mice;a similar effect was observed when 17β‐estradiol was administered to wild‐type (WT) females. The normal rate of ovulation in SULT1E1 KO females may be restored by PGE2. Along this line, ovaries of human Chorionic Gonadotropin (hCG)‐treated SULT1E1 KO mice expressed low levels of cyclooxy‐genase‐2 (COX‐2) and its downstream TSG6;moreover, their ovaries contained a reduced number of expanded cumuli. Our results demonstrate, for the first time, that estrogen inactivation may allow the expression of COX‐2 and subsequent cumulus expansion, enabling normal ovulation. Our findings may be applied to novel treatments of human ovulatory failure.—Gershon, E., Hourvitz, A., Reikhav, S., Maman, E., Dekel, N. Low expression of COX‐2, reduced cumulus expansion, and impaired ovulation in SULT1E1‐deficient mice. FASEB J. 21, 1893–1901 (2007)

Hormonal Regulation of GnRH and LHβ mRNA Expression in Cultured Rat Granulosa Cells

We have recently demonstrated that the rat ovary expresses LHβ, FSHβ, and the common alpha subunit mRNA. In the present report, we studied the regulation of LHβ and of gonadotropin-releasing hormone (GnRH) mRNA expression in granulosa cells that were isolated from immature rats treated with either estrogen or pregnant mare serum gonadotropin (PMSG). In both cell types, GnRH agonist treatment resulted in a decrease in LHβ mRNA expression. However, only in cells derived from PMSG-treated rats, GnRH treatment produced an increase in GnRH mRNA expression. A markedly increased GnRH mRNA expression was also obtained in granulosa cells derived from PMSG-primed rats in response to LH. In addition, FSH reduced the expression of LHβ mRNA in granulosa cells from estrogen-primed rats. These results suggest that the expression of LHβ in the ovary is regulated by locally produced GnRH and by FSH from either the ovary or the pituitary.

Blastocyst implantation failure relates to impaired translational machinery gene expression

Oocyte quality is a well-established determinant of embryonic fate. However, the molecular participants and biological markers that affect and may predict adequate embryonic development are largely elusive. Our aim was to identify the components of the oocyte molecular machinery that part take in the production of a healthy embryo. For this purpose, we used an animal model, generated by us previously, the oocytes of which do not express Cx43 (Cx43(del/del)). In these mice, oogenesis appears normal, fertilisation does occur, early embryonic development is successful but implantation fails. We used magnetic resonance imaging analysis combined with histological examination to characterise the embryonic developmental incompetence. Reciprocal embryo transfer confirmed that the blastocyst evolved from the Cx43(del/del) oocyte is responsible for the implantation disorder. In order to unveil the genes, the impaired expression of which brings about the development of defective embryos, we carried out a genomic screening of both the oocytes and the resulting blastocysts. This microarray analysis revealed a low expression of Egr1, Rpl21 and Eif4a1 in Cx43(del/del) oocytes and downregulation of Rpl15 and Eif4g2 in the resulting blastocysts. We propose that global deficiencies in genes related to the expression of ribosomal proteins and translation initiation factors in apparently normal oocytes bring about accumulation of defects, which significantly compromise their developmental capacity. The blastocysts resulting from such oocytes, which grow within a confined space until implantation, may be unable to generate enough biological mass to allow their expansion. This information could be implicated to diagnosis and treatment of infertility, particularly to IVF.

Polar Body Extrusion and Ovulation

Meiosis is a particular example of cell division, which occurs in germ cells and consists of two consecutive chromosome segregations without an intervening interphase. The two meiotic divisions in oocytes are asymmetric; upon completion of the first round of meiosis oocytes eliminate one set of homologues chromosomes associated with the formation of the first polar body (PBI). This event is immediately followed by their maturation into unfertilized eggs arrested at the second meiotic metaphase (MII). Conclusion of meiosis and generation of a haploid nucleus is triggered by sperm penetration. The oocyte–sperm interaction takes place in the oviduct and is preceded by the release of the MII oocyte from the ovarian follicle during ovulation. Extrusion of PBI is initiated by chromosome condensation and their alignment on a centrally localized spindle, followed by spindle migration to the oocyte periphery and concluded by cytokinesis. These events are controlled by cyclin-dependent kinase 1, the, activity of which is regulated by cyclin B1 availability, determined by its cyclic synthesis and degradation. The MAPK signaling pathway is another key player that controls the migration of the spindle, being responsible for the asymmetric cell division. The precisely timed protein degradation of cyclin B1, as well as that of other regulatory proteins in oocytes resuming meiosis, is executed by the ubiquitin–proteasome pathway. Prior to their proteasomal degradation the substrate proteins undergo polyubiquitination controlled by a series of E2s, followed by the specific E3, also known as APC/C. Impaired regulation of PBI extrusion results in aneuploidy associated with genetic malformations. A compromised mechanism of this process might also be responsible for oocytes aging and the resulting infertility.