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1.
J Math Biol ; 88(1): 1, 2023 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-38006409

RESUMEN

In this study, we consider axonal transport of large cargo vesicles characterised by transient expansion of the axon shaft. Our goal is to formulate a mathematical model which captures the dynamic mechanical interaction of such cargo vesicles with the membrane associated periodic cytoskeletal structure (MPS). It consists of regularly spaced actin rings that are transversal to the longitudinal direction of the axon and involved in the radial contraction of the axon. A system of force balance equations is formulated by which we describe the transversal rings as visco-elastic Kelvin-Voigt elements. In a homogenisation limit, we reformulate the model as a free boundary problem for the interaction of the submembranous MPS with the large vesicle. We derive a non-linear force-velocity relation as a quasi-steady state solution. Computationally we analyse the vesicle size dependence of the transport speed and use an asymptotic approximation to formulate it as a power law that can be tested experimentally.


Asunto(s)
Transporte Axonal , Axones , Axones/metabolismo , Actinas/metabolismo , Modelos Biológicos
2.
J Math Biol ; 85(1): 4, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35788426

RESUMEN

Contraction of actomyosin networks underpins important cellular processes including motility and division. The mechanical origin of actomyosin contraction is not fully-understood. We investigate whether contraction arises on the scale of individual filaments, without needing to invoke network-scale interactions. We derive discrete force-balance and continuum partial differential equations for two symmetric, semi-flexible actin filaments with an attached myosin motor. Assuming the system exists within a homogeneous background material, our method enables computation of the stress tensor, providing a measure of contractility. After deriving the model, we use a combination of asymptotic analysis and numerical solutions to show how F-actin bending facilitates contraction on the scale of two filaments. Rigid filaments exhibit polarity-reversal symmetry as the motor travels from the minus to plus-ends, such that contractile and expansive components cancel. Filament bending induces a geometric asymmetry that brings the filaments closer to parallel as a myosin motor approaches their plus-ends, decreasing the effective spring force opposing motor motion. The reduced spring force enables the motor to move faster close to filament plus-ends, which reduces expansive stress and gives rise to net contraction. Bending-induced geometric asymmetry provides both new understanding of actomyosin contraction mechanics, and a hypothesis that can be tested in experiments.


Asunto(s)
Actinas , Actomiosina , Citoesqueleto de Actina , Contracción Muscular , Miosinas
3.
Biophys J ; 120(18): 4029-4040, 2021 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-34390686

RESUMEN

We use mathematical modeling and computation to investigate how protein friction facilitates contraction of disordered actomyosin networks. We simulate two-dimensional networks using an agent-based model, consisting of a system of force-balance equations for myosin motor proteins and semiflexible actin filaments. A major advantage of our approach is that it enables direct calculation of the network stress tensor, which provides a quantitative measure of contractility. Exploiting this, we use repeated simulations of disordered networks to confirm that both protein friction and actin filament bending are required for contraction. We then use simulations of elementary two-filament systems to show that filament bending flexibility can facilitate contraction on the microscopic scale. Finally, we show that actin filament turnover is necessary to sustain contraction and prevent filament aggregation. Simulations with and without turnover also exhibit contractile pulses. However, these pulses are aperiodic, suggesting that periodic pulsation can only arise because of additional regulatory mechanisms or more complex mechanical behavior.


Asunto(s)
Citoesqueleto de Actina , Actomiosina , Actinas , Citoesqueleto , Fricción , Contracción Muscular , Miosinas
4.
J Math Biol ; 82(4): 29, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33661393

RESUMEN

Neurosecretory cells spatially redistribute their pool of secretory vesicles upon stimulation. Recent observations suggest that in chromaffin cells vesicles move either freely or in a directed fashion by what appears to be a conveyor belt mechanism. We suggest that this observation reflects the transient active transport through molecular motors along cytoskeleton fibres and quantify this effect using a 1D mathematical model that couples a diffusion equation to advection equations. In agreement with recent observations the model predicts that random motion dominates towards the cell centre whereas directed motion prevails in the region abutting the cortical membrane. Furthermore the model explains the observed bias of directed transport towards the periphery upon stimulation. Our model suggests that even if vesicle transport is indifferent with respect to direction, stimulation creates a gradient of free vesicles at first and this triggers the bias of transport in forward direction. Using matched asymptotic expansion we derive an approximate drift-diffusion type model that is capable of quantifying this effect. Based on this model we compute the characteristic time for the system to adapt to stimulation and we identify a Michaelis-Menten-type law describing the flux of vesicles entering the pathway to exocytosis.


Asunto(s)
Células Cromafines , Modelos Biológicos , Vías Secretoras , Vesículas Secretoras , Células Cromafines/metabolismo , Citoplasma/metabolismo , Exocitosis , Microtúbulos/metabolismo , Vesículas Secretoras/metabolismo
5.
Biophys J ; 115(8): 1614-1624, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30268540

RESUMEN

Recent experimental studies of the role of microtubule sliding in neurite outgrowth suggested a qualitative model, according to which kinesin-1 motors push the minus-end-out microtubules against the cell membrane and generate the early cell processes. At the later stage, dynein takes over the sliding, expels the minus-end-out microtubules from the neurites, and pulls in the plus-end-out microtubules that continue to elongate the nascent axon. This model leaves unanswered a number of questions: why is dynein unable to generate the processes alone, whereas kinesin-1 can? What is the role of microtubule dynamics in process initiation and growth? Can the model correctly predict the rates of process growth in control and dynein-inhibited cases? What triggers the transition from kinesin-driven to dynein-driven sliding? To answer these questions, we combine computational modeling of a network of elastic dynamic microtubules and kinesin-1 and dynein motors with measurements of the process growth kinetics and pharmacological perturbations in Drosophila S2 cells. The results verify quantitatively the qualitative model of the microtubule polarity sorting and suggest that dynein-powered elongation is effective only when the processes are longer than a threshold length, which explains why kinesin-1 alone, but not dynein, is sufficient for the process growth. Furthermore, we show that the mechanism of process elongation depends critically on microtubule dynamic instability. Both modeling and experimental measurements show, surprisingly, that dynein inhibition accelerates the process extension. We discuss implications of the model for the general problems of cell polarization, cytoskeletal polarity emergence, and cell process protrusion.


Asunto(s)
Polaridad Celular , Proteínas de Drosophila/metabolismo , Drosophila/crecimiento & desarrollo , Dineínas/metabolismo , Cinesinas/metabolismo , Microtúbulos/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Drosophila/citología , Drosophila/metabolismo , Drosophila/fisiología , Transporte de Proteínas
6.
Biophys J ; 109(9): 1818-29, 2015 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-26536259

RESUMEN

We investigate computationally the self-organization and contraction of an initially random actomyosin ring. In the framework of a detailed physical model for a ring of cross-linked actin filaments and myosin-II clusters, we derive the force balance equations and solve them numerically. We find that to contract, actin filaments have to treadmill and to be sufficiently cross linked, and myosin has to be processive. The simulations reveal how contraction scales with mechanochemical parameters. For example, they show that the ring made of longer filaments generates greater force but contracts slower. The model predicts that the ring contracts with a constant rate proportional to the initial ring radius if either myosin is released from the ring during contraction and actin filaments shorten, or if myosin is retained in the ring, while the actin filament number decreases. We demonstrate that a balance of actin nucleation and compression-dependent disassembly can also sustain contraction. Finally, the model demonstrates that with time pattern formation takes place in the ring, worsening the contractile process. The more random the actin dynamics are, the higher the contractility will be.


Asunto(s)
Actinas/química , Actomiosina/química , Modelos Biológicos , Animales , Fenómenos Biomecánicos , Caenorhabditis elegans , Simulación por Computador , Miosina Tipo II/química , Neurospora crassa , Saccharomycetales
7.
Nat Cell Biol ; 26(9): 1520-1534, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39160291

RESUMEN

Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments.


Asunto(s)
Movimiento Celular , Núcleo Celular , Microtúbulos , Microtúbulos/metabolismo , Animales , Núcleo Celular/metabolismo , Estrés Mecánico , Mecanotransducción Celular , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Ratones , Humanos , Actomiosina/metabolismo , Proteínas de Microfilamentos
8.
PLoS One ; 17(3): e0264521, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35294476

RESUMEN

Through the integration of results from an imaging analysis of intracellular trafficking of labelled neurosecretory vesicles in chromaffin cells, we develop a Markov state model to describe their transport and binding kinetics. Our simulation results indicate that a spatial redistribution of neurosecretory vesicles occurs upon secretagogue stimulation leading vesicles to the plasma membrane where they undergo fusion thereby releasing adrenaline and noradrenaline. Furthermore, we find that this redistribution alone can explain the observed up-regulation of vesicle transport upon stimulation and its directional bias towards the plasma membrane. Parameter fitting indicates that in the deeper compartment within the cell, vesicle transport is asymmetric and characterised by a bias towards the plasma membrane.


Asunto(s)
Células Cromafines , Transporte Biológico , Membrana Celular/metabolismo , Células Cromafines/metabolismo , Vesículas Citoplasmáticas/metabolismo , Cinética
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