A Dynamical Model of Oocyte Maturation Unveils Precisely Orchestrated Meiotic Decisions

Lefranc M (2012) A Dynamical Model of Oocyte Maturation Unveils Precisely Orchestrated Meiotic Decisions. PLoS Comput Biol 8(1): e1002329. doi:10.1371/journal.pcbi.1002329 A Dynamical Model of Oocyte Maturation Unveils Precisely Orchestrated Meiotic Decisions Benjamin Pfeuty 0 Jean-Francois Bodart 0 Ralf Blossey 0 Marc Lefranc 0 Stanislav Shvartsman, Princeton University, United States of America 0 1 Laboratoire de Physique des Lasers, Atomes, et Mole cules, CNRS, UMR8523, Universite Lille 1 Sciences et Technologies, Villeneuve d'Ascq , Franc2eI,nstitut de Recherche Interdisplinaire, CNRS, USR3078 , Universite Lille1 Sciences et Technologies, Villeneuve d'Ascq, France, 3 Laboratoire de Re gulation des Signaux de Division , EA 4479 , Universi teLille 1 Sciences et Technologies , Villeneuve d'Ascq , France Maturation of vertebrate oocytes into haploid gametes relies on two consecutive meioses without intervening DNA replication. The temporal sequence of cellular transitions driving eggs from G2 arrest to meiosis I (MI) and then to meiosis II (MII) is controlled by the interplay between cyclin-dependent and mitogen-activated protein kinases. In this paper, we propose a dynamical model of the molecular network that orchestrates maturation of Xenopus laevis oocytes. Our model reproduces the core features of maturation progression, including the characteristic non-monotonous time course of cyclinCdks, and unveils the network design principles underlying a precise sequence of meiotic decisions, as captured by bifurcation and sensitivity analyses. Firstly, a coherent and sharp meiotic resumption is triggered by the concerted action of positive feedback loops post-translationally activating cyclin-Cdks. Secondly, meiotic transition is driven by the dynamic antagonism between positive and negative feedback loops controlling cyclin turnover. Our findings reveal a highly modular network in which the coordination of distinct regulatory schemes ensures both reliable and flexible cell-cycle decisions. - The mitotic division cycle is the sequence of events by which a growing cell replicates all its components, including DNA, and divides them, after mitosis, into two nearly identical daughter cells [1]. Meiosis is an alternative mode of cell division in which a diploid cell undergoes two successive divisions without intervening DNA synthesis, to create haploid cells called gametes or spores [2]. In vertebrate species, for instance, meiosis occurs during oocyte maturation, which is initiated in response to an hormonal signal with the specificity that oocytes are thereafter arrested, usually at the metaphase stage of MII, awaiting fertilization [3]. Meiotic maturation shares with mitosis many morphological events, such as metaphase and anaphase, as well as regulators such as the cyclin B-Cdk1, known as the M-phase promoting factor (MPF). However, it also involves a unique sequence of decision steps meiotic resumption, transition and arrest - which clearly diverges from the mitotic one (Fig. 1A). Investigating the regulation of meiotic maturation is therefore an opportune strategy to understand the remarkable plasticity of the cell cycle, which unfolds a diversity of decision patterns at different stages of multicellular development. The specific decision pattern of the oocyte meiotic maturation is intimately linked to the tightly controlled temporal dynamics of MPF (Fig. 1B). The rise and the first peak of MPF activity triggers germinal vesicle break down (GVBD) and entry into MI. The transition from MI to MII is typified by an unusual partial decrease of MPF activity followed by an increase and stabilization at a plateau level associated with metaphase II arrest in Xenopus oocytes. The time course of MPF is shaped by a complex web of interaction with other cell-cycle regulators. At the first arrest of Xenopus oocyte in a G2-like state, MPF kinase is stored in an inactive state called pre-MPF in which, among the five isoforms of cyclin B described in this animal model, only cyclin B2 and B5 are found associated to Cdk1 [4]. As during mitosis, MPF activity is primarily regulated by its interaction with a dual protein-phosphatase (Cdc25), a cyclindependent kinase inhibitor (Myt1) and the anaphase promoting complex (APC). During meiotic maturation, this module is supplemented with a layer of control which involves the MAPK (Mitogen Activated Protein Kinase)/ERK(Extracellular Regulated Kinase) pathway, whose main upstream and output components in the context of meiotic maturation are proteins Mos and Rsk, respectively. These components of the MAPK pathway are involved not only in meiotic spindle morphogenesis during oocyte maturation [5] but also at several decision points of the oocyte maturation process including meiotic resumption (G2/MI), meiotic transition (MI/MII) and maintenance of metaphase II arrest [68]. A key advance was to identify Rsk-mediated phosphorylation of APC inhibitor Emi2 as leading to MPF reaccumulation at the MI/MII transition [911]. In turn, MPF tightly controls phosphorylated levels of Mos [12] or Emi2 [13]. Two decades of experimental studies have thus documented manifold levels of interaction between the MPF and Mos/MAPK pathways, whose respective roles in various decision stages of maturation remain difficult to disentangle. In an attempt to clarify the interactions between both pathways, we use a modeling approach which has already been harnessed to gain insight into cell cycle control during animal development, as with the syncytial In the life cycle of sexual organisms, a specialized cell division -meiosis- reduces the number of chromosomes in gametes or spores while fertilization or mating restores the original number. The essential feature that distinguishes meiosis from mitosis (the usual division) is the succession of two rounds of division following a single DNA replication, as well as the arrest at the second division in the case of oocyte maturation. The fact that meiosis and mitosis are similar but different raises several interesting questions: What is the meiosis-specific dynamics of cellcycle regulators? Are there mechanisms which guarantee the occurence of two and only two rounds of division despite the presence of intrinsic and extrinsic noises ? The study of a model of the molecular network that underlies the meiotic maturation process in Xenopus oocytes provides unexpected answers to these questions. On the one hand, the modular organization of this network ensures separate controls of the first and second divisions. On the other hand, regulatory synergies ensure that these two stages are precisely and reliably sequenced during meiosis. We conclude that cells have evolved a sophisticated regulatory network to achieve a robust, albeit flexible, meiotic dynamics. mitotic cycles in Drosophila embryos [14], fertilization process in mammals [15], the oocyte maturation initiation switch [16] but not yet for the whole oocyte meiotic matu (...truncated)