Signaling mechanisms and their regulation during in vivo or in vitro maturation of mammalian oocytes

Abstract

In vitro fertilization (IVF) is currently one of the most effective methods of infertility treatment. An alternative to commonly used ovarian hyperstimulation can become extracorporeal maturation of oocytes (in vitro maturation; IVM). Fertilization and normal development of the embryo depends on the cytoplasmic, nuclear and genomic maturity of the oocyte. The microenvironment of the ovarian follicle and maternal signals, which mediate bidirectional communication between granulosa, cumulus and oocyte cells, influence the growth, maturation and acquisition of oocyte development capability. During oogenesis in mammals, the meiosis is inhibited in the oocyte at the prophase I of the meiotic division due to the high cAMP level. This level is maintained by the activity of C-type natriuretic peptide (CNP, NPPC) produced by granulosa cells. The CNP binds to the NPR2 receptor in cumulus cells and is responsible for the production of cyclic guanosine monophosphate (cGMP). The cGMP penetrating into the oocyte through gap junctions inhibits phosphodiesterase 3A (PDE3A), preventing cAMP hydrolysis responsible for low MPF activity. The LH surge during the reproductive cycle reduces the activity of the CNP/NPR2 complex, which results in a decrease in cGMP levels in cumulus cells and consequently in the oocyte. Reduced cGMP concentration unblocks the hydrolytic activity of PDE3A, which decreases cAMP level inside the oocyte. This leads to the activation of MPF and resumption of meiosis. The latest IVM methods called SPOM, NFSOM or CAPA IVM consist of two steps: prematuration and maturation itself. Taking into account the role of cAMP in inhibiting and then unblocking the maturation of oocytes, they have led to a significant progress in terms of the percentage of mature oocytes in vitro and the proportion of properly developed embryos in both animals and humans.

Quantitative morphokinetic parameters identify novel dynamics of oocyte meiotic maturation and cumulus expansion

“…Notably both the process of meiotic maturation and cumulus expansion can be fully recapitulated outside the ovary when either denuded oocytes or cumulus oocyte complexes (COCs) are matured in vitro, and hallmarks of these processes can be visualized morphologically by transmitted light microscopy [ 5 , 14 ]. First, meiotic maturation is associated with the loss of the germinal vesicle (GV), or delineation of the nucleus due to germinal vesicle breakdown (GVBD), which signifies meiotic resumption and the transition of the oocyte from the prophase I arrest.…”

Regulation of oocyte maturation: Role of conserved ERK signaling

“…During this growth period, oocytes acquire the competencies that are required for oocyte maturation, fertilization, and embryogenesis (Edson et al, 2009). Fully grown oocytes under the influence of a second gonadotrophin, LH, resume meiosis (Figure 2A; Jaffe & Egbert, 2017; Li & Albertini, 2013; Sánchez & Smitz, 2012; Strączyńska et al, 2022).…”

Cyclic Adenosine Monophosphate: A Central Player in Gamete Development and Fertilization, and Possible Target for Infertility Therapies

“…Like spermatogenesis, cAMP is also a central, though not the only, player in mammalian oogenesis from the time point at which ovarian follicles develop an antral cavity, become responsive to the pituitary gonadotropins FSH and LH and initiate the process of oocyte maturation [ 16 ]. Oocyte maturation is a complex process consisting of various molecular regulatory events.…”

“…As mentioned in Section 2 of this article, the intracellular concentration of cAMP depends on an equilibrium between cAMP synthesis, by adenylyl cyclase and degradation by phosphodiesterase 3A (PDE3A). In addition to cAMP, oocyte meiotic maturation is controlled by cyclic guanosine monophosphate (cGMP), both of which are delivered to the oocyte through gap junctions from the surrounding granulosa (cumulus) cells [ 16 ]. Gap junctions are specialized intercellular connections that enable the passage of ions and small molecules, such as cAMP or cGMP, from one cell to another [ 24 ].…”

“…The resumption of meiotic maturation is possible due to the active maturation promoting factor (MPF), a heterodimer consisting of two subunits: the regulatory cyclin B and the catalytic cyclin-dependent kinase (CDK) [ 28 , 29 ]. As the follicle grows, the continuous influx of cAMP into the oocyte maintains a high level of this second messenger in the ooplasm which, in turn, prevents the onset of oocyte meiotic maturation by maintaining a low ooplasmic level of CDK, and thus of MPF [ 16 ], acting through the phosphorylation of other types of kinases, such as Wee1/Myt1 ( Figure 2 ). The effect of cAMP in oocytes is mediated by protein kinase A (PKA) and cAMP response element-binding protein (CREB) pathways [ 22 ].…”