Cooperative success in epithelial public goods games

Cancer cells obtain mutations which rely on the production of diffusible growth factors to confer a fitness benefit. These mutations can be considered cooperative, and studied as public goods games within the framework of evolutionary game theory. The population structure, benefit function and update rule all influence the evolutionary success of cooperators. We model the evolution of cooperation in epithelial cells using the Voronoi tessellation model. Unlike traditional evolutionary graph theory, this allows us to implement global updating, for which birth and death events are spatially decoupled. We compare, for a sigmoid benefit function, the conditions for cooperation to be favoured and/or beneficial for well mixed and structured populations. We find that when population structure is combined with global updating, cooperation is more successful than if there were local updating or the population were well-mixed. Interestingly, the qualitative behaviour for the well-mixed population and the Voronoi tessellation model is remarkably similar, but the latter case requires significantly lower incentives to ensure cooperation.Comment: 29 Pages, 13 Figure

The role of evolutionary game theory in spatial and non-spatial models of the survival of cooperation in cancer: a review

Evolutionary game theory (EGT) is a branch of mathematics which considers populations of individuals interacting with each other to receive pay-offs. An individual’s pay-off is dependent on the strategy of its opponent(s) as well as on its own, and the higher its pay-off, the higher its reproductive fitness. Its offspring generally inherit its interaction strategy, subject to random mutation. Over time, the composition of the population shifts as different strategies spread or are driven extinct. In the last 25 years there has been a flood of interest in applying EGT to cancer modelling, with the aim of explaining how cancerous mutations spread through healthy tissue and how intercellular cooperation persists in tumour-cell populations. This review traces this body of work from theoretical analyses of well-mixed infinite populations through to more realistic spatial models of the development of cooperation between epithelial cells. We also consider work in which EGT has been used to make experimental predictions about the evolution of cancer, and discuss work that remains to be done before EGT can make large-scale contributions to clinical treatment and patient outcomes

Minimum Action Path theory reveals the details of stochastic biochemical transitions out of oscillatory cellular states

Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Tran- sitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending non-locally on the noise. Here we characterize the escape from an oscillatory biochemical state by minimizing the Freidlin-Wentzell action, deriving from it the stochastic spiral exit path from the limit cycle. We also use the minimized action to infer the escape time probability density function

Effect of Iron Availability on Expression of the Bradyrhizobium Japonicum hemA Gene.

Bradyrhizobium japonicum produces delta-aminolevulinic acid, the universal precursor of tetrapyrroles, in a reaction catalyzed by the product of the hemA gene. Expression of the B. japonicum hemA gene is affected by iron availability. Activity of a hemA-lacZ fusion is increased approximately threefold by iron, and RNA analysis indicates that iron regulation is at the level of mRNA accumulation. To our knowledge, this is the first example of an iron-regulated heme biosynthetic gene in prokaryotes

Neuronal differentiation influences progenitor arrangement in the vertebrate neuroepithelium

Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube, in which neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we used experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates the effect of interkinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube

The Stargazin-Related Protein {gamma}7 Interacts with the mRNA-Binding Protein Heterogeneous Nuclear Ribonucleoprotein A2 and Regulates the Stability of Specific mRNAs, Including CaV2.2

The role(s) of the novel stargazin-like {gamma}-subunit proteins remain controversial. We have shown previously that the neuron-specific {gamma}7 suppresses the expression of certain calcium channels, particularly CaV2.2, and is therefore unlikely to operate as a calcium channel subunit. We now show that the effect of {gamma}7 on CaV2.2 expression is via an increase in the degradation rate of CaV2.2 mRNA and hence a reduction of CaV2.2 protein level. Furthermore, exogenous expression of {gamma}7 in PC12 cells also decreased the endogenous CaV2.2 mRNA level. Conversely, knockdown of endogenous {gamma}7 with short-hairpin RNAs produced a reciprocal enhancement of CaV2.2 mRNA stability and an increase in endogenous calcium currents in PC12 cells. Moreover, both endogenous and expressed {gamma}7 are present on intracellular membranes, rather than the plasma membrane. The cytoplasmic C terminus of {gamma}7 is essential for all its effects, and we show that {gamma}7 binds directly via its C terminus to a heterogeneous nuclear ribonucleoprotein (hnRNP A2), which also binds to a motif in CaV2.2 mRNA, and is associated with native CaV2.2 mRNA in PC12 cells. The expression of hnRNP A2 enhances CaV2.2 IBa, and this enhancement is prevented by a concentration of {gamma}7 that alone has no effect on IBa. The effect of {gamma}7 is selective for certain mRNAs because it had no effect on {alpha}2{delta}-2 mRNA stability, but it decreased the mRNA stability for the potassium-chloride cotransporter, KCC1, which contains a similar hnRNP A2 binding motif to that in CaV2.2 mRNA. Our results indicate that {gamma}7 plays a role in stabilizing CaV2.2 mRNA

A CaV2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant

AbstractEpisodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al., 2001; Page et al., 2004). A similar finding has been shown for CaV2.2 (Raghib et al., 2001). We show here that a highly conserved sequence in the cytoplasmic N-terminus is involved in this process, for both CaV2.1 and CaV2.2 channels. Additionally, we were able to interfere with the suppressive effect of an EA2 construct by mutating key N-terminal residues within it. We postulate that the N-terminus of the truncated channel plays an essential part in its interaction with the full-length CaV2.1, which prevents the correct folding of the wild-type channel. In agreement with this, we were able to disrupt the interaction between EA2 and the full length channel by co-expressing a free N-terminal peptide

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Altres ajuts: CERCA Programme/Generalitat de Cataluny