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Review
. 2015 Sep 20:8:11-21.
doi: 10.4137/BCI.S28596. eCollection 2015.

Selective Regulation of Oocyte Meiotic Events Enhances Progress in Fertility Preservation Methods

Onder Celik  1 , Nilufer Celik  2 , Sami Gungor  3 , Esra Tustas Haberal  4 , Suleyman Aydin  5
Affiliations
Review

Selective Regulation of Oocyte Meiotic Events Enhances Progress in Fertility Preservation Methods

Onder Celik et al. Biochem Insights. .

Abstract

Following early embryonic germ cell migration, oocytes are surrounded by somatic cells and remain arrested at diplotene stage until luteinizing hormone (LH) surge. Strict regulation of both meiotic arrest and meiotic resumption during dormant stage are critical for future fertility. Inter-cellular signaling system between the somatic compartment and oocyte regulates these meiotic events and determines the follicle quality. As well as the collected number of eggs, their qualities are also important for in vitro fertilization (IVF) outcome. In spontaneous and IVF cycles, germinal vesicle (GV)-stage oocytes, premature GV breakdown, and persistence of first meiotic arrest limit the reproductive performance. Likewise, both women with premature ovarian aging and young cancer women are undergoing chemoradiotherapy under the risk of follicle loss because of unregulated meiotic events. Understanding of oocyte meiotic events is therefore critical for the prevention of functional ovarian reserve. High levels of cyclic guanosine monophophate (cGMP), cyclic adenosine monophophate (cAMP) and low phosphodiesterase (PDE) 3A enzyme activity inside the oocyte are responsible for maintaining of meiotic arrest before the LH surge. cGMP is produced in the somatic compartment, and natriuretic peptide precursor C (Nppc) and natriuretic peptide receptor 2 (Npr2) regulate its production. cGMP diffuses into the oocyte and reduces the PDE3A activity, which inhibits the conversion of cAMP to the 5'AMP, and cAMP levels are enhanced. In addition, oocyte itself has the ability to produce cAMP. Taken together, accumulation of cAMP inside the oocyte induces protein kinase activity, which leads to the inhibition of maturation-promoting factor and meiotic arrest also continues. By stimulating the expression of epidermal growth factor, LH inhibits the Nppc/Npr2 system, blocks cGMP synthesis, and initiates meiotic resumption. Oocytes lacking the functional of this pathway may lead to persistence of the GV oocyte, which reduces the number of good quality eggs. Selective regulation of somatic cell signals and oocyte meiotic events enhance progress in fertility preservation methods, which may give us the opportunity to prevent follicle loss in prematurely aging women and young women with cancer are undergoing chemoradiotherapy.

Keywords: Nppc/Npr2; PDEs; cAMP; cGMP; fertility preservation; oocyte meiosis.

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Figures

Figure 1
Figure 1
Abbreviated pathways to illustrate inhibitory signals maintaining meiotic arrest before the LH surge. (A) Mild hypoxia within the somatic cells induces hypoxanthine (HX) synthesis, which increases the synthesis of inosine, which is the responsible substrate for GTP and cGMP synthesis. Nppc/Npr2 system controls cGMP production in the somatic cells. Npr2 is activated by the Nppc and produces cGMP from GTP. cGMP diffuses into the oocyte via gap junctions (two thick red lines). In the absence of LH surge, gap junctions undergo dephosphorylation and become activate. cGMP inhibits the PDE3A, which inhibits the hydrolysis of cAMP into 5′AMP. 8-Br-cGMP, a cGMP analog, also blocks the PDE3A activity. cGMP synthesis in somatic cells may overcome the hydrolytic activity of PDE5 enzyme (dashed red line). Note the compartmentalization of the PDEs. GPRs induce Gs expression and activate AC, which stimulates cAMP synthesis. Accumulation of cAMP inside the oocyte mediates meiotic arrest by increasing PKA. Activation or inhibition of PKA by cAMP regulates the functions of the Cdc25 and the Wee1B/Myt1. While the Cdc25 dephosphorylates Cdk1, Wee1B/Myt1 kinase phosphorylates it. E2, FSH, and ODPFs (GDF-9, BMP-15) contribute to maintain first meiotic arrest by inducing Npr2 mRNA in cumulus cells. ODPFs also control the activity of IMPDH. The action of IMPDH, which converts IMP into GMP, is blocked by mizoribine and mycophenolic acid. High PP1 activities inside the oocyte prevent nuclear envelope dissolution. Pharmacological inhibition of MPF with the roscovitine blocks GVBD. High follicular fluid (FF) CNP levels were noted before ovulation. (B) Abbreviated pathways to illustrate the role of LH surge on meiotic resumption. LH acts on the mural cells because of the absence of functional LHRs in the cumulus cells and oocyte. LH surge leads to disruption of arresting mechanisms, which would result in the activation of PDE3A. Inhibition of the Nppc/Npr2 by LH surge leads to a reduction in cGMP synthesis. LH surge mediates the phosphorylation (P) of connexin 43 and 37, leading to the closure of the gap junctions (thick red lines). Phosphorylation of gap-junction is a MAPK-dependent process. LH decreases granulosa cell nitric oxide expression and activates cGMP synthesis. LH surge also initiates the dephosphorylation of Cdk1 and the MPF becomes active. MPF phosphorylates both PP1 and nuclear envelope, which causes GVBD. OA increases the phosphorylated PP1 (inactive PP1) levels and leads to GVBD. Taken together, both the synthesis and transfer of cGMP into the oocyte are blocked. Decline in the cGMP concentration inside the oocyte allows PDE3A to hydrolyze cAMP into 5′AMP, leading to meiotic resumption. Yellow and blue arrows indicate excitatory signals, and red lines indicate inhibitory signals. See text for details. (Adapted from Refs. –.)
Figure 1
Figure 1
Abbreviated pathways to illustrate inhibitory signals maintaining meiotic arrest before the LH surge. (A) Mild hypoxia within the somatic cells induces hypoxanthine (HX) synthesis, which increases the synthesis of inosine, which is the responsible substrate for GTP and cGMP synthesis. Nppc/Npr2 system controls cGMP production in the somatic cells. Npr2 is activated by the Nppc and produces cGMP from GTP. cGMP diffuses into the oocyte via gap junctions (two thick red lines). In the absence of LH surge, gap junctions undergo dephosphorylation and become activate. cGMP inhibits the PDE3A, which inhibits the hydrolysis of cAMP into 5′AMP. 8-Br-cGMP, a cGMP analog, also blocks the PDE3A activity. cGMP synthesis in somatic cells may overcome the hydrolytic activity of PDE5 enzyme (dashed red line). Note the compartmentalization of the PDEs. GPRs induce Gs expression and activate AC, which stimulates cAMP synthesis. Accumulation of cAMP inside the oocyte mediates meiotic arrest by increasing PKA. Activation or inhibition of PKA by cAMP regulates the functions of the Cdc25 and the Wee1B/Myt1. While the Cdc25 dephosphorylates Cdk1, Wee1B/Myt1 kinase phosphorylates it. E2, FSH, and ODPFs (GDF-9, BMP-15) contribute to maintain first meiotic arrest by inducing Npr2 mRNA in cumulus cells. ODPFs also control the activity of IMPDH. The action of IMPDH, which converts IMP into GMP, is blocked by mizoribine and mycophenolic acid. High PP1 activities inside the oocyte prevent nuclear envelope dissolution. Pharmacological inhibition of MPF with the roscovitine blocks GVBD. High follicular fluid (FF) CNP levels were noted before ovulation. (B) Abbreviated pathways to illustrate the role of LH surge on meiotic resumption. LH acts on the mural cells because of the absence of functional LHRs in the cumulus cells and oocyte. LH surge leads to disruption of arresting mechanisms, which would result in the activation of PDE3A. Inhibition of the Nppc/Npr2 by LH surge leads to a reduction in cGMP synthesis. LH surge mediates the phosphorylation (P) of connexin 43 and 37, leading to the closure of the gap junctions (thick red lines). Phosphorylation of gap-junction is a MAPK-dependent process. LH decreases granulosa cell nitric oxide expression and activates cGMP synthesis. LH surge also initiates the dephosphorylation of Cdk1 and the MPF becomes active. MPF phosphorylates both PP1 and nuclear envelope, which causes GVBD. OA increases the phosphorylated PP1 (inactive PP1) levels and leads to GVBD. Taken together, both the synthesis and transfer of cGMP into the oocyte are blocked. Decline in the cGMP concentration inside the oocyte allows PDE3A to hydrolyze cAMP into 5′AMP, leading to meiotic resumption. Yellow and blue arrows indicate excitatory signals, and red lines indicate inhibitory signals. See text for details. (Adapted from Refs. –.)
Figure 2
Figure 2
Abbreviated pathways to illustrate the LH effect on the Nppc/Npr2 system. EGF-LGF potentiates the effectiveness of LH signal, induces the expression of EGF-R, and inhibits the Npr2 activity. Likewise, after the LH surge, expression of mitogen-activated protein kinase (MAPK) increases and activates the EGF-R. Phosphorylation of EGF-R activates it. Decline in the expression levels of Npr2 after LH signal takes place by three possible mechanisms. First, activation of EGF-R increases the calcium levels inside the cumulus cells and reduces the Npr2 activity. Second, induction of EGF-R activity decreases Npr2 expression in the cumulus cells by means of dephosphorylation reactions. Third, by activating EGF-R, LH increases the secretion of amphiregulin, which leads to downregulation of the Nppc expression. Moreover, EGF-R activation inhibits the Nppc mRNA expression in the somatic cells. Taken together, EGF- and MAPK-mediated LH action in the Nppc/Npr2 system blocks the conversion of GTP to cGMP, and the oocyte undergoes meiotic resumption. Concentration of nuclear phosphorylated PP1 (inactive PP1) is elevated in OA-mediated GVBD. LH surge induces the activation of MAPK, which phosphorylates the gap-junction proteins and leads to their closure. Cdk1 inhibits PP1 by phosphorylating it at Thr320. Cdk1 also phosphorylates the nuclear envelope and initiates GVBD. Periantral mural cells signify weak Npr2 activity. When the distance from oocyte membrane increases, Npr2 activity in periantral mural cells decreases. (Adapted from Refs. –.)
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