Novel signaling mechanisms in the ovary during oocyte maturation and ovulation
ABSTRACT During the peri-ovulatory period, the gonadotropin LH triggers major changes in both the somatic and germ cell compartments of the ovarian follicle. The oocyte completes the meiotic cell cycle to become a fertilizable egg, and dramatic changes in gene expression and secretion take place in the somatic compartment of the follicle in preparation for follicular rupture and oocyte release. The concerted changes are regulated by activation of intracellular signaling pathways as well as paracrine and autocrine regulatory loops. This review will provide a summary of the current knowledge of the molecular events triggered by LH focusing mostly on the signaling pathways required for oocyte maturation.
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- "Cumulus cell production of extracellular matrix molecules is a hallmark of cumulus cell differentiation, is required for the ovulatory cascade, and the expression of key associated genes are mediated by EGFR signaling (Conti et al., 2012). We measured cumulus expansion and expression of relevant genes such as HAS2, TNFIP6 and PTGS2 within cumulus cells of small antral folliclederived COCs treated with or without AREG in the presence or absence of B15 þG9 and/or cAMP (Fig. 5). "
ABSTRACT: Oocytes acquire developmental competence with progressive folliculogenesis. Cumulus oocyte complexes (COCs) from small antral follicles have inherent low competence and are poorly responsive to amphiregulin (AREG) which normally mediates oocyte maturation and ovulation. Using low competence porcine COCs, in an in vitro AREG-induced oocyte maturation system, the combined exposure to N(6),2'-O-dibutyryladenosine 3':5' cyclic monophosphate (cAMP) and bone morphogenetic protein 15 (B15) and growth differentiation factor 9 (G9) was necessary to enhance the rate of oocyte meiotic maturation and blastocyst formation. Furthermore, the combination of cAMP+B15+G9 enabled AREG-stimulated cumulus expansion and increased expression of the matrix-related genes HAS2, TNFIPA6 and PTGS2. Additionally, the combination enhanced p-ERK1/2 which is downstream of the EGF receptor. The enhanced nuclear maturation and blastocyst formation rates with the combinational treatment were ablated by an EGF receptor phosphorylation inhibitor. These results indicate that cAMP and oocyte-secreted factors cooperate to promote EGF receptor functionality in developing COCs, representing a key component of the acquisition of oocyte developmental competence. Copyright © 2015. Published by Elsevier Inc.Developmental Biology 05/2015; 403(2). DOI:10.1016/j.ydbio.2015.05.008 · 3.55 Impact Factor
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- "Connexins (CX) are a family of transmembrane proteins that connect to form gap junctions; channels which allow direct exchange of ions and small molecules between adjacent cells and which are involved in cell proliferation, differentiation, cell survival, oocyte maturation, meiotic resumption and death (Gershon et al., 2008; Conti et al., 2012; Kar et al., 2012). Eight CX proteins are expressed in ovaries encoded by the Cx26, Cx30.3, Cx32, Cx37, Cx40, Cx43, Cx45 and Cx57 genes (Grazul-Bilska et al., 1997; Kidder and Mhawi, 2002). "
ABSTRACT: The ovarian gap junction proteins alpha 4 (GJA4 or connexin 37; CX37), alpha 1 (GJA1 or connexin 43; CX43) and gamma 1 (GJC1 or connexin 45; CX45) are involved in cell communication and folliculogenesis. 7,12-dimethylbenz[a]anthracene (DMBA) alters Cx37 and Cx43 expression in cultured neonatal rat ovaries. Additionally, obesity has an additive effect on DMBA-induced ovarian cell death and follicle depletion, thus, we investigated in vivo impacts of obesity and DMBA on CX protein levels. Ovaries were collected from lean and obese mice aged 6, 12, 18, or 24 wks. A subset of 18 wk old mice (lean and obese) were dosed with sesame oil or DMBA (1mg/kg; ip) for 14days and ovaries collected 3days thereafter. Cx43 and Cx45 mRNA and protein levels decreased (P<0.05) after 18 wks while Cx37 mRNA and protein levels decreased (P<0.05) after 24 wks in obese ovaries. Cx37 mRNA and antral follicle protein staining intensity were reduced (P<0.05) by obesity while total CX37 protein was reduced (P<0.05) in DMBA exposed obese ovaries. Cx43 mRNA and total protein levels were decreased (P<0.05) by DMBA in both lean and obese ovaries while basal protein staining intensity was reduced (P<0.05) in obese controls. Cx45 mRNA, total protein and protein staining intensity level were decreased (P<0.05) by obesity. These data support that obesity temporally alters gap junction protein expression and that DMBA-induced ovotoxicity may involve reduced gap junction protein function. Copyright © 2014 Elsevier Inc. All rights reserved.Toxicology and Applied Pharmacology 11/2014; 282(1):1-8. DOI:10.1016/j.taap.2014.10.020 · 3.71 Impact Factor
- "CG= mural granulosa cells; CC= cumulus cells; Oo= oocyte; PDE= phosphodiesterase, EGFR= EGF receptor; GPR= receptor linked to the protein G; NPPC= natriuretic peptide, NPR2= receptor of natriuretic peptide; P= phosphorylation, Cx= conexin. Modified from Conti et al., 2012. "
Article: Control of oocyte maturation[Show abstract] [Hide abstract]
ABSTRACT: Oocyte maturation is a complex process involving nuclear and cytoplasmic maturation. The nuclear maturation is a chromosomal segregation and the cytoplasmic maturation involves the reorganization of the cytoplasmic organelles, mRNA transcription and storage of proteins to be used during fertilization and early embryo development. The mechanism of oocyte maturation in vivo and in vitro still are not totally understood. However it is generally accepted that the second messenger cyclic adenosine monophosphate (cAMP) plays a critical role in the maintenance of meiotic blockage of mammalian oocytes. A relative increase in the level of cAMP within the oocyte is essential for maintaining meiosis block, while a decrease in cAMP oocyte concentration allows the resumption of meiosis. The oocyte cAMP concentration is regulated by a balance of two types of enzymes: adenylate cyclase (AC) and phosphodiesterases (PDEs), which are responsible for the synthesis and degradation of cAMP, respectively. After being synthesized by AC in cumulus cells, cAMP are transferred to the oocyte through gap junctions. Thus, specific subtypes PDEs are able to inhibit or attenuate the spontaneous meiotic maturation of oocytes with PDE4 primarily involved in the metabolism of cAMP in granulosa cells and PDE3 in the oocyte. Although the immature oocytes can resume meiosis in vitro, after being removed from antral follicles, cytoplasmic maturation seems to occur asynchronously with nuclear maturation. Therefore, knowledge of the oocyte maturation process is fundamental for the development of methodologies to increase the success of in vitro embryo production and to develop treatments for various forms of infertility. This review will present current knowledge about the maintenance of the oocyte in prophase arrest, and the resumption of meiosis during oocyte maturation, focusing mainly on the changes that take place in the oocyte.Animal reproduction 09/2014; 11(3). · 0.78 Impact Factor