Modeling Microtubule-Based Transport and Anchoring of mRNA

Ciocanel, Maria-Veronica; Sandstede, Björn; Jeschonek, Samantha P.; Mowry, Kimberly L.

doi:10.1137/18m1186083

Cited by 10 publications

(20 citation statements)

References 56 publications

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“…To further probe the role of microtubule trafficking, we compared the experimentally observed cytoplasmic distributions of different mRNA species with results from a one-dimensional diffusion–advection model (Supplementary Fig. 11A), in which microtubule trafficking is represented by advection [ 12 , 14 ]. This simple model closely recapitulated the cytosolic distributions of mRNA for SL membrane proteins ( Gja1 [Cx43], Scn5a [Na V 1.5], and Cacna1c [Ca V 1.2]) under control conditions (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Using a well-established approach [ 12 , 14 ], we simulated the distribution of mRNA in the cytoplasm using a simple trafficking model, the 1D advection–diffusion partial differential equation where is the concentration of the i type mRNA. The equation is defined on the non-dimensional spatial domain [0,1], for which x = 0 and 1 represents the edge of the nucleus and the cell membrane, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

et al. 2021

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It is widely assumed that synthesis of membrane proteins, particularly in the heart, follows the classical secretory pathway with mRNA translation occurring in perinuclear regions followed by protein trafficking to sites of deployment. However, this view is based on studies conducted in less-specialized cells, and has not been experimentally addressed in cardiac myocytes. Therefore, we undertook direct experimental investigation of protein synthesis in cardiac tissue and isolated myocytes using single-molecule visualization techniques and a novel proximity-ligated in situ hybridization approach for visualizing ribosome-associated mRNA molecules for a specific protein species, indicative of translation sites. We identify here, for the first time, that the molecular machinery for membrane protein synthesis occurs throughout the cardiac myocyte, and enables distributed synthesis of membrane proteins within sub-cellular niches where the synthesized protein functions using local mRNA pools trafficked, in part, by microtubules. We also observed cell-wide distribution of membrane protein mRNA in myocardial tissue from both non-failing and hypertrophied (failing) human hearts, demonstrating an evolutionarily conserved distributed mechanism from mouse to human. Our results identify previously unanticipated aspects of local control of cardiac myocyte biology and highlight local protein synthesis in cardiac myocytes as an important potential determinant of the heart’s biology in health and disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

et al. 2021

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“…That the transport machinery is sensitive to motor organization opens several possible directions of future work. First, cargos in the cell exist in a microtubule network with a specific architecture [16,[43][44][45]. The current work focused on exploring interaction with a single MT, but could readily be extended.…”

Section: Future Model Extensionsmentioning

confidence: 99%

Diffusion of kinesin motors on cargo can enhance binding and run lengths during intracellular transport

Bovyn¹,

Reddy²,

Gross³

et al. 2019

Preprint

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Cellular cargos, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. In the cell, it is unclear how motors are coordinated to achieve transport outcomes that are cargo-specific. One possibility is that transport is modulated by differences in organization and mobility of motors on the cargo's surface. We use mechanochemical 3D computational modeling to compare different motor anchoring modes, and find that organizational changes can optimize for different objectives. Cargos with clustered motors are transported efficiently, but are slow to bind to microtubules. Cargos with motors dispersed rigidly on their surface bind microtubules quickly, but are transported inefficiently. Cargos with freely-diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results point to a functional role for observed changes in motor organization on cargos, and suggest motor diffusivity as a control point for transport, either by modulation of adaptor proteins or changes in lipid composition. Author summaryThe molecular motors of the kinesin family are responsible for moving the parts of cells 1 to their subcellular destinations, organizing the cell interior. Computational modeling 2 has historically played an important role in understanding how these motors work. But, 3 strikingly, most models assume the subcellular cargos have rigid surfaces. Simulating 4 fluid surfaces is more challenging but more applicable to biological cargo. In this work, 5 we build a computational model of molecular motor transport of cargo with fluid 6 surfaces. Surface fluidity gives cargo transport new properties, like enhanced transport 7 efficiency, and the ability to push against opposing forces. Because the effects of surface 8 fluidity vary strongly with some of the properties of the cargo, like its size, our results 9 hint at one of the ways that the same transport machinery can distinguish different 10 cargo despite using the same motors. 13 kinesin and dynein superfamilies to transport organelles and other cargo along 14 microtubules. Despite having only a limited set of cargo transport motors (kinesin-1, 15 kinesin-2 and kinesin-3 families [1], along with cytoplasmic dynein), different cargos are 16 transported to different locations, even though they are transported along the same set 17 of microtubule "roads". For example, under normal conditions COS-7 cells direct lipid 18 droplets toward microtubule plus end, localizing them near the plasma membrane, and 19 mitochondria toward the minus end, localizing them near the nucleus. Under glucose 20 starvation, localization of both organelles changes to spread them out around the cell, 21 allowing them to come into contact with each other [2]. How do cells achieve these 22 cargo-specific routing outcomes? In some cases, cells use molecular specificity to achieve 23 cargo specificity, such as using specific linkers or cargo-bound regulators [3,4]. 24 However, recent experiment...

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“…The effective diffusivity is given, from an equivalent long-time effective dynamical description for intracellular transport derived by Lyapunov-Schmidt reduction on the low wavenumber asymptotics of the Fourier transform of Eq. (1) in Ciocanel et al (2017Ciocanel et al ( , 2018, by…”

Section: Pde Methods For Markovian Switchingmentioning

confidence: 95%

“…( 1 ) in Ciocanel et al. ( 2017 , ( 2018 ), by where denotes the Hadamard product (component-wise multiplication of vectors). Here , and is the restriction of to its range (vectors orthogonal to ).…”

Section: Introductionmentioning

confidence: 99%

Renewal Reward Perspective on Linear Switching Diffusion Systems in Models of Intracellular Transport

et al. 2020

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In many biological systems, the movement of individual agents is characterized having multiple qualitatively distinct behaviors that arise from a variety of biophysical states. For example, in cells the movement of vesicles, organelles, and other intracellular cargo is affected by their binding to and unbinding from cytoskeletal filaments such as microtubules through molecular motor proteins. A typical goal of theoretical or numerical analysis of models of such systems is to investigate effective transport properties and their dependence on model parameters. While the effective velocity of particles undergoing switching diffusion dynamics is often easily characterized in terms of the long-time fraction of time that particles spend in each state, the calculation of the effective diffusivity is more complicated because it cannot be expressed simply in terms of a statistical average of the particle transport state at one moment of time. However, it is common that these systems are regenerative, in the sense that they can be decomposed into independent cycles marked by returns to a base state. Using decompositions of this kind, we calculate effective transport properties by computing the moments of the dynamics within each cycle and then applying renewal reward theory. This method provides a useful alternative large-time analysis to direct homogenization for linear advection–reaction–diffusion partial differential equation models. Moreover, it applies to a general class of semi-Markov processes and certain stochastic differential equations that arise in models of intracellular transport. Applications of the proposed renewal reward framework are illustrated for several case studies such as mRNA transport in developing oocytes and processive cargo movement by teams of molecular motor proteins.

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Modeling Microtubule-Based Transport and Anchoring of mRNA

Cited by 10 publications

References 56 publications

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes

Diffusion of kinesin motors on cargo can enhance binding and run lengths during intracellular transport

Renewal Reward Perspective on Linear Switching Diffusion Systems in Models of Intracellular Transport

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