Progesterone-Induced Oocyte Maturation in X. laevis
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Progesterone-Induced Oocyte Maturation in X. laevis

Female fertility requires precise regulation of oocyte meiosis. Females from nearly every species of animal are born with their full complement of oocytes; however, these immature oocytes remain arrested in Prophase-I of meiosis, till the time of ovulation (Ref.1). During this long period of Prophase arrest, the oocyte becomes enclosed into a follicle, and the follicle-enclosed oocyte grows, accumulates molecular reserves and acquires its competence in an orderly manner for completion of meiotic divisions, fertilization and early embryonic development. The Prophase block is released when oocyte growth is completed (i.e., at the time of ovulation) (Ref.2). Just before ovulation, Gonadotropins stimulate ovarian follicular development, which in turn promotes oocytes to mature, by reentering the meiotic cycle. Oocyte maturation is defined as the reinitiation and completion of the Meiosis-I, subsequent progression to Metaphase of Meiosis-II, and the nuclear and cytoplasmic processes, which become essential for fertilization and early embryo development. The nucleus of an oocyte is the GV (Germinal Vesicle), and the most striking event of the reinitiation of meiosis is the disappearance or breakdown of the GV, known as, GVBD (Germinal Vesicle Breakdown) (Ref.3). Completion of the first meiotic division takes place when oocytes have undergone extensive growth in cellular interaction with the granulosa and theca cells. Once Meiosis-I is completed, the second meiotic division is initiated, and the oocytes remain arrested in Metaphase of Meiosis-II until maturation. These mature oocytes are now competent for ovulation and subsequent fertilization, after which the final stages of meiosis are completed (Ref.1 & 4).

The amphibian oocyte represents one of the best-characterized models for oocyte maturation. In Xenopus laevis, immature oocytes are physiologically arrested in the first meiotic Prophase at the G2/M border and resume meiosis when Gonadotropins stimulate surrounding follicle cells, causing them to secrete the steroid hormone Progesterone. Ovarian Progesterone is the natural trigger of amphibian oocyte maturation, commonly assessed by GVBD (Ref. 2 & 4). This process transforms the immature oocyte into a fertilizable egg. In amphibians, oocyte growth is divided into six stages, from Stage-I (50 ┬Ám in diameter) to the full-grown stage VI oocyte (>1.2 mm in diameter). Only Stage-VI oocytes are responsive to Progesterone. The unresponsiveness of smaller oocytes to Progesterone prevents premature meiotic maturation and fertilization, a mechanism contributing to the successful fertilization and embryonic development. Progesterone induces the meiotic division in Xenopus oocytes by binding to its receptors: mPR (Membrane Progesterone Receptor) and/or iPR (Intracellular Progesterone Receptor), and is independent of gene transcription (Ref.5). During meiotic maturation, oocytes are transcriptionally repressed and all necessary proteins are translated from preexisting, maternally derived mRNAs. The resumption of meiosis (maturation) occurs through a rapid action of Progesterone. This involves the inhibition of the oocyte AC (Adenylyl Cyclase) and reduction of the intracellular cAMP (Cyclic Adenosine 3,5-Monophosphate) concentration, as well as the activation of MAPK (Mitogen-Activated Protein Kinase) and  PLK (Polo-Like Kinase) pathways. These pathways converge to promote dephosphorylation and activation of the cytoplasmic Cyclin-B-CDC2 (Cell Division Control Protein-2) complex [also known as MPF (Maturation Promoting Factor)], the enzyme that catalyzes entry into the M-phase of Meiosis-I (Ref.1 & 6).

The membrane-bound mPR is a seven-transmembrane protein with the characteristics of a  GPCR (G-Protein-Coupled Receptor). When bound to Progesterone, this receptor blocks the activity of AC, the enzyme that catalyzes production of the intracellular second-messenger cAMP, through activation of G-AlphaI or inhibition of G-AlphaS (Ref.2 & 7). This stimulation of mPR is followed by a decrease in cAMP-dependent PKA (Protein Kinase-A) activity and activation of a cascade of multiple protein kinases: Mos, Raf, MAPK and activation of CDC25C (Tyrosine Phosphatase-CDC25C) through PLKK1 (Polo-Like Kinase Kinase-1), and Plx1 (Polo-Like Kinase-1). Progesterone also induces rapid changes in the activities of several other enzymes in this system. It activates the Serine/Threonine Kinase Eg2 (Serine/Threonine-Protein Kinase Eg2), which phosphorylates CPEB (Cytoplasmic Polyadenylation Element Binding Factor), a protein bound to the cytoplasmic polyadenylated element at the 3 untranslated region of Mos mRNA (messenger RNA) (Ref.8). Phosphorylation of CPEB by Eg2 stimulates the cytoplasmic polyadenylation of Mos mRNA, leading to its translational activation. Newly translated Mos protein, a MAPKKK (MAP Kinase Kinase Kinase), activates preexisting MEK (Mitogen-Activated Extracellular Signal-regulated Protein Kinase Kinase), which in turn enhances the activity of MAPK. This results in the activation of MPF via Myt1 inhibiton. Mos also associates with Myt1 independently of MAPK Cascade activation. This interaction could facilitate Myt1 inactivation by restricting the access of Myt1 phosphatase and/or by Myt1 phosphorylation by Mos on some sites and therefore enhancing MPF activation (Ref.9 & 10). In Xenopus oocytes, the cytoplasmic localization of iPR contributes to MAPK activation during mPR-induced oocyte maturation (Ref.2). After binding to Progesterone, iPR is recruited to the protein tyrosine kinase Src, which induces activation of the MAPK signaling pathway. iPR also activates MAPK pathway through the activation of Ras and Raf. A target of MAPK, p90RSK (Ribosomal Protein S6 Kinase) operates in Meiosis-I to promote MPF activation by phosphorylating and inactivating Myt1, which favors formation of the activated Cell Cycle Complex, MPF.  p90RSK also functions in Meiosis-II  by inhibiting Cyclin-B degradation by the APC Anaphase-Promoting Complex) and by contributing to the suppression of mitotic exit after CDC2  inactivation through a role in CSF (Cytostatic Factor)-mediated Metaphase arrest (Ref.6 & 11).

All these events lead to activation of MPF. Full-grown oocytes contain pre-MPF where CDC2  is maintained inactive by Thr14 and Tyr15 phosphorylation. Progesterone induces activation of MPF by a post-transcriptional mechanism ending in the activatory dephosphorylation of CDC2 by CDC25C (Ref.2 & 6). Activated MPF then induces GVBD through nuclear envelope disassembly, comprising chromosome condensation accompanied by spindle formation and profound cytoskeletal reorganization, resulting in the subsequent oocyte maturation. During Progesterone-induced maturation, oocytes undergo remarkable structural reorganization. The early events include progressive size reduction of the microvilli, flattening of the plasma membrane, movement of cortical granules away from the plasma membrane, and a significant decrease in the density of intramembrane particles. These events make the oocytes competent for fertilization and early embryonic development (Ref.1 & 11).