Abstract
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 cyclin-Cdks, 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.
Highlights
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]
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 meiosis II (MII), awaiting fertilization [3]
The unknown rate constants of the model are estimated by fitting the qualitative model behavior to the available data, including the well-characterized temporal profile of M-phase promoting factor (MPF) activity during the meiotic maturation (Fig. 1B) as well as the bistable behavior of the MAPK modules and the oscillatory dynamics of the MPF-anaphase promoting complex (APC) module (Methods)
Summary
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]. Meiotic maturation shares with mitosis many morphological events, such as metaphase and anaphase, as well as regulators such as the cyclin B-Cdk, known as the M-phase promoting factor (MPF). It 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 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
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