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Paracrine and autocrine regulation of EGF-like factors in cumulus oocyte complexes (COCs) and granulosa cells: key roles for prostanglandin synthase 2 (Ptgs2) and progesterone receptor (Pgr). Shimada M et al. The molecular bridges that link the LH surge with functional changes in cumulus cells that possess few LH receptors are being unraveled. Herein we document that EGF-like factors amphiregulin (Areg), epiregulin (Ereg) and betacellulin (Btc) are induced in cumulus oocyte complexes (COCs) by autocrine and paracrine mechanisms that involve the actions of prostaglandins (PGs) and progesterone receptor (PGR). Areg and Ereg mRNA and protein levels were reduced significantly in COCs and ovaries collected from prostagandin synthase 2 (Ptgs2) null mice and Pgr null (PRKO) mice at 4 h and 8 h post-hCG, respectively. In cultured COCs, FSH/forskolin induced Areg mRNA within 0.5 h that peaked at 4 h, a process blocked by inhibitors of p38MAPK (SB203580), MEK1 (PD98059) and PTGS2 (NS398) but not PKA (KT5720). Conversely, AREG but not FSH induced Ptsg2 mRNA at 0.5 h with peak expression of Ptgs2 and Areg mRNAs at 4 h, processes blocked by the EGF receptor tyrosine kinase inhibitor AG1478, PD98059 and NS398. PGE2 reversed the inhibitory effects of AG1478 on AREG induced expression of Areg but not Ptgs2, placing Ptgs2 downstream of EGF-R signaling. PMA and adenovirally expressed PGRA synergistically induced Areg mRNA in granulosa cells. In COCs AREG not only induced genes that impact matrix formation but also genes involved in steroidogenesis (StAR, Cyp11a1) and immune cell-like functions (Pdcd1, Runx1, Cd52). Collectively, FSH mediated induction of Areg mRNA via p38MAPK precedes AREG induction of Ptgs2 mRNA via ERK1/2. PGs acting via PTGER2 in cumulus cells provide a secondary, autocrine pathway to regulate expression of Areg in COCs showing critical functional links between G-protein coupled receptor and growth factor receptor pathways in ovulating follicles.
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CD52 Is Synthesized in Cumulus Cells and Secreted into the Cumulus Matrix During Ovulation. Hasegawa A et al. Problem Early studies have shown that an antibody to male reproductive tissue CD52 is a pathogenic factor of infertility. The molecule contains a unique carbohydrate antigen that induces antibodies interfering with sperm function. However, the characteristic properties of CD52 in female reproductive tissues are not known. We examined the expression and localization of CD52 in mature expanded cumulus masses. Method of study Mouse cumulus oocyte complexes were collected from C57B1/6; DBA/2 F1 female mice having a superovulation treatment. Human cumulus cells were obtained from infertile patients taking in vitro fertilization-embryo transfer treatment under informed consent. CD52 messenger RNA (mRNA) and protein were detected using RT-PCR, quantitative PCR, western blotting and immunohistochemical methods. Results CD52 mRNA was found both in the human and mouse cumulus cells. Mouse CD52 mRNA was detected in cumulus cells but not oocytes and significantly increased after ovulation. The expression of the molecule was also confirmed at the protein level. Immunostaining with anti CD52 peptide antibody revealed that CD52 is present in cumulus cells and the extracellular matrix. Conclusion We first showed the expression of CD52 in human cumulus cells. CD52 has some functional roles around fertilization in females as well as in males.
Gene expression profiles of cumulus cell oocyte complexes (COCs) during ovulation reveal cumulus cells express neuronal and immune-related genes: Does this expand their role in the ovulation process
Hernandez-Gonzalez I, et al ?
Ovulation is a complex process initiated by the preovulatory LH surge, characterized by cumulus oocyte complex (COC) expansion and completed by the release of a mature oocyte. Although many ovarian genes that impact ovulation have been identified, we hypothesized that genes selectively expressed in COCs would be overlooked by approaches using whole ovary or granulosa cell samples. RNA isolated from COCs collected from preovulatory follicles of eCG-primed mice and at selected times following hCG treatment was subjected to microarray analyses and results confirmed by RT-PCR analyses, Western blotting and immunofluorescent studies. A remarkable number of genes was up-regulated in COCs including Areg, Ereg, and Btc. Several genes selectively expressed in cumulus cells compared with granulosa cells were related to neuronal (Mbp, Tnc, Nts) or immune (Alcam, Pdcd1, Cd34, Cd52 and Cxcr4) cell function. In addition to Sfrp2, other members of the Wnt/Fzd family (Sfrp4, Fdz1 and Fdz2) were expressed in COCs. Thus, there is a cumulus cell-specific, terminal differentiation process. Furthermore, immunofluorescent analyses documented that cumulus cells are highly mitotic for 4-8 h after hCG and then cease dividing in association with reduced levels of Ccnd2 mRNA. Other down-regulated genes included: Cyp19a1, Fshr, Inhb, and the oocyte factors Zp1-3 and Gja4. In summary, the vast number of matrix, neuronal and especially immune cell-related genes identified by the gene profiling data of COCs constitutes strong and novel evidence that cumulus cells possess a repertoire of immune functions that could be far greater than simply mediating an inflammatory-like response.
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