Multistability and dynamic transitions of intracellular Min protein patterns.
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ABSTRACT:
SUBMITTER: Wu F
PROVIDER: S-EPMC4923923 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Min proteins constitute the best-studied model system for pattern formation in cell biology. We theoretically predict and experimentally show that the propagation direction of in vitro Min protein patterns can be controlled by a hydrodynamic flow of the bulk solution. We find downstream propagation of Min wave patterns for low MinE:MinD concentration ratios, upstream propagation for large ratios, but multistability of both propagation directions in between. Whereas downstream propagation can be described by a minimal model that disregards MinE conformational switching, upstream propagation can be reproduced by a reduced switch model, where increased MinD bulk concentrations on the upstream side promote protein attachment. Our study demonstrates that a differential flow, where bulk flow advects protein concentrations in the bulk, but not on the surface, can control surface-pattern propagation. This suggests that flow can be used to probe molecular features and to constrain mathematical models for pattern-forming systems.
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Project description:The bacterial Min protein system provides a major model system for studying reaction-diffusion processes in biology. Here we present the first in vitro study of the Min system in fully confined three-dimensional chambers that are lithography-defined, lipid-bilayer coated and isolated through pressure valves. We identify three typical dynamical behaviors that occur dependent on the geometrical chamber parameters: pole-to-pole oscillations, spiral rotations, and traveling waves. We establish the geometrical selection rules and show that, surprisingly, Min-protein spiral rotations govern the larger part of the geometrical phase diagram. Confinement as well as an elevated temperature reduce the characteristic wavelength of the Min patterns, although even for confined chambers with a bacterial-level viscosity, the patterns retain a ~5 times larger wavelength than in vivo. Our results provide an essential experimental base for modeling of intracellular Min gradients in bacterial cell division as well as, more generally, for understanding pattern formation in reaction-diffusion systems.
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Project description:The boundary of a cell defines the shape and scale of its subcellular organization. However, the effects of the cell's spatial boundaries as well as the geometry sensing and scale adaptation of intracellular molecular networks remain largely unexplored. Here, we show that living bacterial cells can be 'sculpted' into defined shapes, such as squares and rectangles, which are used to explore the spatial adaptation of Min proteins that oscillate pole-to-pole in rod-shaped Escherichia coli to assist cell division. In a wide geometric parameter space, ranging from 2?×?1?×?1 to 11?×?6?×?1??m(3), Min proteins exhibit versatile oscillation patterns, sustaining rotational, longitudinal, diagonal, stripe and even transversal modes. These patterns are found to directly capture the symmetry and scale of the cell boundary, and the Min concentration gradients scale with the cell size within a characteristic length range of 3-6??m. Numerical simulations reveal that local microscopic Turing kinetics of Min proteins can yield global symmetry selection, gradient scaling and an adaptive range, when and only when facilitated by the three-dimensional confinement of the cell boundary. These findings cannot be explained by previous geometry-sensing models based on the longest distance, membrane area or curvature, and reveal that spatial boundaries can facilitate simple molecular interactions to result in far more versatile functions than previously understood.
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Project description:Protein patterning is vital for many fundamental cellular processes. This raises two intriguing questions: Can such intrinsically complex processes be reduced to certain core principles and, if so, what roles do the molecular details play in individual systems? A prototypical example for protein patterning is the bacterial Min system, in which self-organized pole-to-pole oscillations of MinCDE proteins guide the cell division machinery to midcell. These oscillations are based on cycling of the ATPase MinD and its activating protein MinE between the membrane and the cytoplasm. Recent biochemical evidence suggests that MinE undergoes a reversible, MinD-dependent conformational switch from a latent to a reactive state. However, the functional relevance of this switch for the Min network and pattern formation remains unclear. By combining mathematical modeling and in vitro reconstitution of mutant proteins, we dissect the two aspects of MinE's switch, persistent membrane binding and a change in MinE's affinity for MinD. Our study shows that the MinD-dependent change in MinE's binding affinity for MinD is essential for patterns to emerge over a broad and physiological range of protein concentrations. Mechanistically, our results suggest that conformational switching of an ATPase-activating protein can lead to the spatial separation of its distinct functional states and thereby confer robustness on an intracellular protein network with vital roles in bacterial cell division.
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Project description:Rotating waves (RW) bifurcating from the axisymmetric basic magnetized spherical Couette (MSC) flow are computed by means of Newton-Krylov continuation techniques for periodic orbits. In addition, their stability is analysed in the framework of Floquet theory. The inner sphere rotates while the outer is kept at rest and the fluid is subjected to an axial magnetic field. For a moderate Reynolds number Re?=?103 (measuring inner rotation), the effect of increasing the magnetic field strength (measured by the Hartmann number Ha) is addressed in the range Ha?(0,?80) corresponding to the working conditions of the HEDGEHOG experiment at Helmholtz-Zentrum Dresden-Rossendorf. The study reveals several regions of multistability of waves with azimuthal wavenumber m?=?2,?3,?4, and several transitions to quasi-periodic flows, i.e modulated rotating waves. These nonlinear flows can be classified as the three different instabilities of the radial jet, the return flow and the shear layer, as found in the previous studies. These two flows are continuously linked, and part of the same branch, as the magnetic forcing is increased. Midway between the two instabilities, at a certain critical Ha, the non-axisymmetric component of the flow is maximum.
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Project description:Fully-connected triads (FCTs), such as the Oct4-Sox2-Nanog triad, have been implicated as recurring transcriptional motifs embedded within the regulatory networks that specify and maintain cellular states. To explore the possible connections between FCT topologies and cell fate determinations, we employed computational network screening to search all possible FCT topologies for multistability, a dynamic property that allows the rise of alternate regulatory states from the same transcriptional network. The search yielded a hierarchy of FCTs with various potentials for multistability, including several topologies capable of reaching eight distinct stable states. Our analyses suggested that complete auto-activation is an effective indicator for multistability, and, when gene expression noise was incorporated into the model, the networks were able to transit multiple states spontaneously. Different levels of stochasticity were found to either induce or disrupt random state transitioning with some transitions requiring layovers at one or more intermediate states. Using this framework we simulated a simplified model of induced pluripotency by including constitutive overexpression terms. The corresponding FCT showed random state transitioning from a terminal state to the pluripotent state, with the temporal distribution of this transition matching published experimental data. This work establishes a potential theoretical framework for understanding cell fate determinations by connecting conserved regulatory modules with network dynamics. Our results could also be employed experimentally, using established developmental transcription factors as seeds, to locate cell lineage specification networks by using auto-activation as a cipher.
| S-EPMC4109943 | biostudies-literature
Project description:Self-organisation of Min proteins is responsible for the spatial control of cell division in Escherichia coli, and has been studied both in vivo and in vitro. Intriguingly, the protein patterns observed in these settings differ qualitatively and quantitatively. This puzzling dichotomy has not been resolved to date. Using reconstituted proteins in laterally wide microchambers with a well-controlled height, we experimentally show that the Min protein dynamics on the membrane crucially depend on the micro chamber height due to bulk concentration gradients orthogonal to the membrane. A theoretical analysis shows that in vitro patterns at low microchamber height are driven by the same lateral oscillation mode as pole-to-pole oscillations in vivo. At larger microchamber height, additional vertical oscillation modes set in, marking the transition to a qualitatively different in vitro regime. Our work reveals the qualitatively different mechanisms of mass transport that govern Min protein-patterns for different bulk heights and thus shows that Min patterns in cells are governed by a different mechanism than those in vitro.
| S-EPMC8175580 | biostudies-literature
Project description:BackgroundUnderstanding what factors lead to youth polysubstance use (PSU) patterns and how the transitions between use patterns can inform the design and implementation of PSU prevention programs. We explore the dynamics of PSU patterns from a large cohort of Canadian secondary school students using machine learning techniques.MethodsWe employed a multivariate latent Markov model (LMM) on COMPASS data, with a linked sample (N = 8824) of three-annual waves, Wave I (WI, 2016-17, as baseline), Wave II (WII, 2017-18), and Wave III (WIII, 2018-19). Substance use indicators, i.e., cigarette, e-cigarette, alcohol and marijuana, were self-reported and were categorized into never/occasional/current use.OutcomesFour distinct use patterns were identified: no-use (S1), single-use of alcohol (S2), dual-use of e-cigarettes and alcohol (S3), and multi-use (S4). S1 had the highest prevalence (60.5%) at WI, however, S3 became the prominent use pattern (32.5%) by WIII. Most students remained in the same subgroup over time, particularly S4 had the highest transition probability (0.87) across the three-wave. With time, those who transitioned typically moved towards a higher use pattern, with the most and least likely transition occurring S2→S3 (0.45) and S3→S2 (<0.01), respectively. Among all covariates being examined, truancy, being measured by the # of classes skipped, significantly affected transition probabilities from any low→high (e.g., ORS2→S4 = 2.41, 95% CI [2.11, 2.72], p < 0.00001) and high→low (e.g., ORS3→S1 = 0.38, 95% CI [0.33, 0.44], p < 0.00001) use directions over time. Older students, blacks (vs. whites), and breakfast eaters were less likely to transition from low→high use direction. Students with more weekly allowance, with more friends that smoked, longer sedentary time, and attended attended school unsupportive to resist or quit drug/alcohol were more likely to transition from low→high use direction. Except for truancy, all other covariates had inconsistent effects on the transition probabilities from the high→low use direction.InterpretationThis is the first study to ascertain the dynamics of use patterns and factors in youth PSU utilizing LMM with population-based longitudinal health surveys, providing evidence in developing programs to prevent youth PSU.FundingThe Applied Health Sciences scholarship; the Microsoft AI for Good grant; the Canadian Institutes of Health Research, Health Canada, the Canadian Centre on Substance Abuse, the SickKids Foundation, the Ministère de la Santé et des Services sociaux of the province of Québec.
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Project description:The E. coli MinDE oscillator is a paradigm for protein self-organization and gradient formation. Previously, we reconstituted Min protein wave patterns on flat membranes as well as gradient-forming pole-to-pole oscillations in cell-shaped PDMS microcompartments. These oscillations appeared to require direct membrane interaction of the ATPase activating protein MinE. However, it remained unclear how exactly Min protein dynamics are regulated by MinE membrane binding. Here, we dissect the role of MinE's membrane targeting sequence (MTS) by reconstituting various MinE mutants in 2D and 3D geometries. We demonstrate that the MTS defines the lower limit of the concentration-dependent wavelength of Min protein patterns while restraining MinE's ability to stimulate MinD's ATPase activity. Strikingly, a markedly reduced length scale-obtainable even by single mutations-is associated with a rich variety of multistable dynamic modes in cell-shaped compartments. This dramatic remodeling in response to biochemical changes reveals a remarkable trade-off between robustness and versatility of the Min oscillator.
| S-EPMC5473585 | biostudies-literature
Project description:In multistability, a constant stimulus induces alternating perceptual interpretations. For many forms of visual multistability, the transition from one interpretation to another ("perceptual switch") is accompanied by a dilation of the pupil. Here we ask whether the same holds for auditory multistability, specifically auditory streaming. Two tones were played in alternation, yielding four distinct interpretations: the tones can be perceived as one integrated percept (single sound source), or as segregated with either tone or both tones in the foreground. We found that the pupil dilates significantly around the time a perceptual switch is reported ("multistable condition"). When participants instead responded to actual stimulus changes that closely mimicked the multistable perceptual experience ("replay condition"), the pupil dilated more around such responses than in multistability. This still held when data were corrected for the pupil response to the stimulus change as such. Hence, active responses to an exogeneous stimulus change trigger a stronger or temporally more confined pupil dilation than responses to an endogenous perceptual switch. In another condition, participants randomly pressed the buttons used for reporting multistability. In Study 1, this "random condition" failed to sufficiently mimic the temporal pattern of multistability. By adapting the instructions, in Study 2 we obtained a response pattern more similar to the multistable condition. In this case, the pupil dilated significantly around the random button presses. Albeit numerically smaller, this pupil response was not significantly different from the multistable condition. While there are several possible explanations-related, e.g., to the decision to respond-this underlines the difficulty to isolate a purely perceptual effect in multistability. Our data extend previous findings from visual to auditory multistability. They highlight methodological challenges in interpreting such data and suggest possible approaches to meet them, including a novel stimulus to simulate the experience of perceptual switches in auditory streaming.
| S-EPMC8177413 | biostudies-literature