Robustness of meiotic dynamics to signal and kinetic parameter variability.

<p>Dynamical trajectories of [MPF] followed in time (top panels), and in state space ([MPF],[APC]) (bottom panels) during maturation in presence of two types of random variability. (<b>A</b>) Variations of progesterone input profile (green lines: pulse-like; red lines: step-like) and amplitude. (<b>B</b>) Variations of all kinetic parameter values with a (orange lines). Thick black lines correspond to the control case depicted in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#pcbi-1002329-g001" target="_blank">Fig. 2</a>. In bottom panel of (<b>A</b>) is indicated the maturation stage (MetI: metaphase of meiosis I, AnaI: anaphase of meiosis I; MI-MII: transition from meiosis I to meiosis II; MetII: metaphase of meisosis II) associated with distinct portion of the state-space trajectory.</p

Examples of oocyte maturation defect phenotypes.

<p>Pharmacological or antisense treatments impacting the activity of several specific proteins lead to various sorts of maturation defect phenotypes as reported in the literature. B-type cyclin is abbreviated as <i>Cyc</i>. Changing specific parameters of the model allows to simulate these phenotypes, which is also shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#pcbi-1002329-g005" target="_blank">Fig. 5</a>.</p

Identification of two network modules using parameter sensitivity analysis.

<p>(<b>A</b>) Schematic representation of the first sensitivity measure, where , and correspond to variations in timing of first MPF peak and in MPF levels at the MI/MII transition and at the metaphase II arrest, respectively, in response to parameter variations. Right-side panels show two examples where only or indicators is sensitive to the parameter changed. (<b>B</b>) Schematic representation of the second sensitivity measure, where and correspond to displacements of saddle points I and IV in the bifurcation diagram of <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#pcbi-1002329-g002" target="_blank">Fig. 2B</a>, in response to parameter variations. Right-side panels show two examples in which only one saddle-node bifurcation point is sensitive to the parameter changed. (<b>C</b>) Systematic calculation of normalized sensitivities for all interaction parameters of the model (see Eqs.1 and 2 with , , , and ). The top panel shows the total sensitivities and . The bottom panel shows the normalized sensitivities (left bar) and (right bar). Asterisks (resp., circles) indicate when (resp., ). (<b>D</b>,<b>E</b>) The initial network can be redrawn as two networks that control different stages of maturation process, namely the G2/MI and MI/MII transitions. The and signs indicate the presence of positive and negative feedback loops, respectively.</p

Model parameter values.

<p>Parameter values result from adjusting qualitatively the behavior of various configurations of the model to experimental data (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#s4" target="_blank">Methods</a>). Note that the actual value of can be arbitrary chosen.</p

Simulated MPF time courses associated with meiotic maturation defects.

<p>Time course of MPF activity in normal condition (<i>dashed line</i>) and various altered conditions (<i>full line</i>). (<b>A</b>) Ablation of cyclin synthesis (). (<b>B</b>) Ablation of Mos synthesis (). (<b>C</b>) Ablation of Plx1 activity . (<b>D</b>) Ablation of MEK activity (). (<b>E</b>) Overexpression of Emi2 (). (<b>F</b>) Ablation of Emi2 synthesis ().</p

Feedback design principles of oocyte meiotic maturation.

<p>(<b>A</b>)The auto-amplification positive-feedback loop switches on MPF activity (Red). (<b>B</b>) Coupled positive-feedback loops ensure a coherent switch of the MPF and MAPK activities (black). (<b>C</b>) The negative-feedback loop linking MPF and APC (blue) triggers a transient decrease of MPF activity that does not impact the high MAPK activities maintained by independent positive-feedback loops. (<b>D</b>) Delayed activation of a positive-feedback loop mediated by Emi2 (green) antagonizes the negative-feedback loop, so as to fully reactivate MPF.</p

Strategy for the adjustment of model parameters.

<p>(<b>A</b>) The constraint that the MAPK module (upper panel) must behave as a bistable switch (example of a bifurcation diagram in middle panel) allows one to determine a parameter domain in a 7-dimensional parameter space (bottom panel). An arbitrary parameter set is chosen within this domain. (<b>B</b>) The constraint that the MPF-APC module (upper panel) must behave as an oscillator under constant stimulation or be excitable upon a transient stimulation, which is associated with a saddle-node bifurcation on an invariant circle (example of a bifurcation diagram in middle panel), allows one to determine a parameter domain in a 15-dimensional parameter space (bottom panel). An arbitrary parameter set is chosen within this domain. (<b>C</b>) The constraint that the whole network (upper panel) must display a maturation behavior associated with a specific time course of its components (MPF time course as an example in middle panel) allows one to determine a parameter domain in the remaining 32-dimensional parameter space (bottom panel). An arbitrary parameter set is chosen within this domain.</p

Equations of the model.

<p>Dynamic and steady-state equations associated with the network shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#pcbi-1002329-g001" target="_blank">Fig. 1C</a> (see also <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#s4" target="_blank">Methods</a>).</p

Complex bistable dynamics during meiotic maturation.

<p>(<b>A</b>) Time courses of various protein concentrations in response to a lasting progesterone pulse. We use the parameter set given by <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002329#pcbi-1002329-t002" target="_blank">Table 2</a>. In the top panel, time profiles are represented using a grayscale code which is normalized so that the maximal concentration of each protein corresponds to black. In the bottom panel, activities of MPF (<i>red</i>), ERK (<i>brown</i>), APC (<i>blue</i>) and Emi2 (<i>green</i>) are shown as functions of time, together with the constant progesterone signal (<i>dashed line</i>). (<b>B</b>) Bifurcation diagram showing the steady state of MPF activity as a function of progesterone level. Black solid and dotted lines are associated with stable and unstable equilibria, respectively. Circles indicates the occurence of a saddle-node bifurcation. The red dashed line shows the dynamic trajectory of MPF during progesterone-induced maturation.</p

Hydrogen Sulfide Donor Protects Porcine Oocytes against Aging and Improves the Developmental Potential of Aged Porcine Oocytes

<div><p>Porcine oocytes that have matured in in vitro conditions undergo the process of aging during prolonged cultivation, which is manifested by spontaneous parthenogenetic activation, lysis or fragmentation of aged oocytes. This study focused on the role of hydrogen sulfide (H₂S) in the process of porcine oocyte aging. H₂S is a gaseous signaling molecule and is produced endogenously by the enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). We demonstrated that H₂S-producing enzymes are active in porcine oocytes and that a statistically significant decline in endogenous H₂S production occurs during the first day of aging. Inhibition of these enzymes accelerates signs of aging in oocytes and significantly increases the ratio of fragmented oocytes. The presence of exogenous H₂S from a donor (Na₂S.9H₂O) significantly suppressed the manifestations of aging, reversed the effects of inhibitors and resulted in the complete suppression of oocyte fragmentation. Cultivation of aging oocytes in the presence of H₂S donor positively affected their subsequent embryonic development following parthenogenetic activation. Although no unambiguous effects of exogenous H₂S on MPF and MAPK activities were detected and the intracellular mechanism underlying H₂S activity remains unclear, our study clearly demonstrates the role of H₂S in the regulation of porcine oocyte aging.</p></div