Bistability in the actin cortex

Multi-color fluorescence imaging experiments of wave forming Dictyostelium cells have revealed that actin waves separate two domains of the cell cortex that differ in their actin structure and phosphoinositide composition. We propose a bistable model of actin dynamics to account for these experimental observation. The model is based on the simplifying assumption that the actin cytoskeleton is composed of two distinct network types, a dendritic and a bundled network. The two structurally different states that were observed in experiments correspond to the stable fixed points in the bistable regime of this model. Each fixed point is dominated by one of the two network types. The experimentally observed actin waves can be considered as trigger waves that propagate transitions between the two stable fixed points

Computational Models of the Notch Network Elucidate Mechanisms of Context-dependent Signaling

The Notch signaling pathway controls numerous cell fate decisions during development and adulthood through diverse mechanisms. Thus, whereas it functions as an oscillator during somitogenesis, it can mediate an all-or-none cell fate switch to influence pattern formation in various tissues during development. Furthermore, while in some contexts continuous Notch signaling is required, in others a transient Notch signal is sufficient to influence cell fate decisions. However, the signaling mechanisms that underlie these diverse behaviors in different cellular contexts have not been understood. Notch1 along with two downstream transcription factors hes1 and RBP-Jk forms an intricate network of positive and negative feedback loops, and we have implemented a systems biology approach to computationally study this gene regulation network. Our results indicate that the system exhibits bistability and is capable of switching states at a critical level of Notch signaling initiated by its ligand Delta in a particular range of parameter values. In this mode, transient activation of Delta is also capable of inducing prolonged high expression of Hes1, mimicking the “ON” state depending on the intensity and duration of the signal. Furthermore, this system is highly sensitive to certain model parameters and can transition from functioning as a bistable switch to an oscillator by tuning a single parameter value. This parameter, the transcriptional repression constant of hes1, can thus qualitatively govern the behavior of the signaling network. In addition, we find that the system is able to dampen and reduce the effects of biological noise that arise from stochastic effects in gene expression for systems that respond quickly to Notch signaling

Insights into the Molecular Evolution of the PDZ/LIM Family and Identification of a Novel Conserved Protein Motif

The PDZ and LIM domain-containing protein family is encoded by a diverse group of genes whose phylogeny has currently not been analyzed. In mammals, ten genes are found that encode both a PDZ- and one or several LIM-domains. These genes are: ALP, RIL, Elfin (CLP36), Mystique, Enigma (LMP-1), Enigma homologue (ENH), ZASP (Cypher, Oracle), LMO7 and the two LIM domain kinases (LIMK1 and LIMK2). As conventional alignment and phylogenetic procedures of full-length sequences fell short of elucidating the evolutionary history of these genes, we started to analyze the PDZ and LIM domain sequences themselves. Using information from most sequenced eukaryotic lineages, our phylogenetic analysis is based on full-length cDNA-, EST-derived- and genomic- PDZ and LIM domain sequences of over 25 species, ranging from yeast to humans. Plant and protozoan homologs were not found. Our phylogenetic analysis identifies a number of domain duplication and rearrangement events, and shows a single convergent event during evolution of the PDZ/LIM family. Further, we describe the separation of the ALP and Enigma subfamilies in lower vertebrates and identify a novel consensus motif, which we call ‘ALP-like motif’ (AM). This motif is highly-conserved between ALP subfamily proteins of diverse organisms. We used here a combinatorial approach to define the relation of the PDZ and LIM domain encoding genes and to reconstruct their phylogeny. This analysis allowed us to classify the PDZ/LIM family and to suggest a meaningful model for the molecular evolution of the diverse gene architectures found in this multi-domain family

Monotone and near-monotone biochemical networks

Monotone subsystems have appealing properties as components of larger networks, since they exhibit robust dynamical stability and predictability of responses to perturbations. This suggests that natural biological systems may have evolved to be, if not monotone, at least close to monotone in the sense of being decomposable into a “small” number of monotone components, In addition, recent research has shown that much insight can be attained from decomposing networks into monotone subsystems and the analysis of the resulting interconnections using tools from control theory. This paper provides an expository introduction to monotone systems and their interconnections, describing the basic concepts and some of the main mathematical results in a largely informal fashion

Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK

Jun N-terminal kinases (JNKs) are implicated in various neuropathological conditions. However, physiological roles for JNKs in neurons remain largely unknown, despite the high expression level of JNKs in brain. Here, using bioinformatic and biochemical approaches, we identify the AMPA receptor GluR2L and GluR4 subunits as novel physiological JNK substrates in vitro, in heterologous cells and in neurons. Consistent with this finding, GluR2L and GluR4 associate with specific JNK signaling components in the brain. Moreover, the modulation of the novel JNK sites in GluR2L and GluR4 is dynamic and bi-directional, such that phosphorylation and de-phosphorylation are triggered within minutes following decreases and increases in neuronal activity, respectively. Using live-imaging techniques to address the functional consequence of these activity-dependent changes we demonstrate that the novel JNK site in GluR2L controls reinsertion of internalized GluR2L back to the cell surface following NMDA treatment, without affecting basal GluR2L trafficking. Taken together, our results demonstrate that JNK directly regulates AMPA-R trafficking following changes in neuronal activity in a rapid and bi-directional manner

Unfertilized Xenopus Eggs Die by Bad-Dependent Apoptosis under the Control of Cdk1 and JNK

Ovulated eggs possess maternal apoptotic execution machinery that is inhibited for a limited time. The fertilized eggs switch off this time bomb whereas aged unfertilized eggs and parthenogenetically activated eggs fail to stop the timer and die. To investigate the nature of the molecular clock that triggers the egg decision of committing suicide, we introduce here Xenopus eggs as an in vivo system for studying the death of unfertilized eggs. We report that after ovulation, a number of eggs remains in the female body where they die by apoptosis. Similarly, ovulated unfertilized eggs recovered in the external medium die within 72 h. We showed that the death process depends on both cytochrome c release and caspase activation. The apoptotic machinery is turned on during meiotic maturation, before fertilization. The death pathway is independent of ERK but relies on activating Bad phosphorylation through the control of both kinases Cdk1 and JNK. In conclusion, the default fate of an unfertilized Xenopus egg is to die by a mitochondrial dependent apoptosis activated during meiotic maturation

Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System

In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7

Memory in Microbes: Quantifying History-Dependent Behavior in a Bacterium

Memory is usually associated with higher organisms rather than bacteria. However, evidence is mounting that many regulatory networks within bacteria are capable of complex dynamics and multi-stable behaviors that have been linked to memory in other systems. Moreover, it is recognized that bacteria that have experienced different environmental histories may respond differently to current conditions. These “memory” effects may be more than incidental to the regulatory mechanisms controlling acclimation or to the status of the metabolic stores. Rather, they may be regulated by the cell and confer fitness to the organism in the evolutionary game it participates in. Here, we propose that history-dependent behavior is a potentially important manifestation of memory, worth classifying and quantifying. To this end, we develop an information-theory based conceptual framework for measuring both the persistence of memory in microbes and the amount of information about the past encoded in history-dependent dynamics. This method produces a phenomenological measure of cellular memory without regard to the specific cellular mechanisms encoding it. We then apply this framework to a strain of Bacillus subtilis engineered to report on commitment to sporulation and degradative enzyme (AprE) synthesis and estimate the capacity of these systems and growth dynamics to ‘remember’ 10 distinct cell histories prior to application of a common stressor. The analysis suggests that B. subtilis remembers, both in short and long term, aspects of its cell history, and that this memory is distributed differently among the observables. While this study does not examine the mechanistic bases for memory, it presents a framework for quantifying memory in cellular behaviors and is thus a starting point for studying new questions about cellular regulation and evolutionary strategy