Balance of microtubule stiffness and cortical tension determines the size of blood cells with marginal band across species

Dmitrieff, Serge; Alsina, Adolfo; Mathur, Aastha; Nédélec, François

doi:10.1073/pnas.1618041114

Cited by 56 publications

(63 citation statements)

References 45 publications

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“…Both mouse and human platelets follow a similar scaling law, approximately "4 ∝ R 9 where R is the marginal band size ( = "# /2 for resting platelets) and "4 is the fluorescence intensity of labeled microtubules. A different law ( "4 ∝ R < ) was observed across species for erythrocytes with a marginal band (Dmitrieff et al, 2017), but it was already noted that platelets did not obey this scaling. The physical arguments provided to explain an exponent of 4 therefore do not hold for the data presented here, at the scale of single species.…”

Section: Discussionmentioning

confidence: 93%

“…It has been previously proposed that the size of a platelet is defined by a mechanical equilibrium between the elastic bending forces of the microtubule bundle and cortical tension of membrane associated cytoskeleton ( (Thon et al, 2012) (Dmitrieff et al, 2017)).…”

Section: Initial Length Determines Marginal Band Coiling Propensitymentioning

confidence: 99%

“…At longer times, all MBs become flat again. Indeed from purely mechanical arguments (Dmitrieff et al, 2017), one can expect larger MBs to be more prone to coiling than the smaller ones.…”

Section: Initial Length Determines Marginal Band Coiling Propensitymentioning

confidence: 99%

“…The first one is that activation induces cortical contraction leading to mechanical compression of the MB. In this scenario, the MB initially behaves like a passive elastic coil constrained by the actin cortex (Dmitrieff, Alsina, Mathur, & Nedelec, 2017). Alternatively, platelet activation would activate some microtubule associated motors, possibly kinesins acting within the ring, or dynein molecules anchored at the cortex.…”

Section: Introductionmentioning

confidence: 99%

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Cytoskeleton mechanics determine resting size and activation dynamics of platelets

Mathur¹,

Correia²,

Dmitrieff³

et al. 2018

Preprint

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Highlights• Platelet size scales consistently with amount of polymerized tubulin in both mouse and human.• Polymerized actin is required for ADP-induced marginal band coiling.• Upon activation, the marginal band exhibits a reversible visco-elastic response involving shortening.• Larger marginal bands have a higher propensity to coil than shorter ones. In briefThe cytoskeleton is adapted to platelet size and its mechanical properties determine propensity of a platelet to undergo morphological changes in response to agonists. Summary (150 words)Platelets are cell fragments of various size that help maintain hemostasis. The way platelets respond during a clotting process is known to depend on their size, with important physiological consequences. We characterized the cytoskeleton of platelets as a function of their size. In resting Human and Mice platelets, we find a quadradic law between the size of a platelet and the amount of microtubule polymer it contains. We further estimate the length and number of microtubules in the marginal band using Electron and Super-resolution microscopy. In platelets activated with ADP, the marginal band coils as a consequence of cortical contraction driven by actin. We observe that this elastic coiling response is accompanied by a reversible shortening of the marginal band.Moreover, larger platelets have a higher propensity to coil. These results establish the dynamic equilibrium that is responsible for platelet size and differential response on a more quantitative level.

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Section: Discussionmentioning

confidence: 93%

Section: Initial Length Determines Marginal Band Coiling Propensitymentioning

confidence: 99%

“…At longer times, all MBs become flat again. Indeed from purely mechanical arguments (Dmitrieff et al, 2017), one can expect larger MBs to be more prone to coiling than the smaller ones.…”

Section: Initial Length Determines Marginal Band Coiling Propensitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytoskeleton mechanics determine resting size and activation dynamics of platelets

Mathur¹,

Correia²,

Dmitrieff³

et al. 2018

Preprint

Self Cite

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“…Of the many cell systems in which careful regulation of tubulin modification is required for healthy function, the role of the tubulin code in the generation of blood platelets from their progenitors, megakaryocytes (MKs) remains relatively poorly understood. Platelets are the smallest component of peripheral blood, and circulate as anucleate cells with an archetypal discoid shape maintained by a microtubule marginal band (12,13). The activation of platelets involves a tightly regulated rearrangement of the cytoskeleton which results in a series of shape changes (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Post-translational polymodification of β1 tubulin regulates motor protein localisation in platelet production and function

Khan

Slater

Maclachlan

et al. 2019

Preprint

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Key Points 1• The platelet specific -1 tubulin (encoded by TUBB1) is polyglutamylated and polyglycylated in platelet producing iPSC-2 derived megakaryocytes (MKs). 3 • The platelet marginal band is polyglutamylated upon activation. 4 • Polymodification in both MKs and platelets impact motor protein localisation. 5• Patients with C-terminal TUBB1 variants demonstrate macrothrombocytopenia, and the CRISPR mediated knock out of 6 TUBB1 in iPSC-MKs results in a complete loss of proplatelet production. 7• 3 unrelated families with mutations in TTLL10 report moderate to severe bleeding and increased mean platelet volume 8 (MPV), suggesting polyglycylation through TTLL10 is required for healthy platelet production. 9• A system of reversible polymodifications mediated through the graded expression of modifying enzymes (TTLLs and 10 CCPs) throughout MK maturation is required for proplatelet formation and subsequent platelet function. 11 Introduction 12Microtubules are large, cytoskeletal filaments vital to a host of critical functions including cell division, signalling, cargo 13 transport, motility, and function(1-3). Despite their ubiquitous expression and high structural conservation, microtubules also 14 drive unique morphologies and functions in specialist cell types like ciliated cells, spermatozoa, and neurons (4, 5). The question 15 of how filaments expressed in every cell in the body can facilitate complex and highly unique behaviours like neurotransmitter 16 release and retinal organisation has been addressed by the tubulin code. This is a paradigm which accounts for the specialisation 17 of microtubules and their organisation by describing a mechanism in which particular cells express lineage restricted isoforms 18 of tubulin. These cell specific isoforms are then subject to a series of post-translational modifications which alter the mechanical 19 properties of microtubules, and their capacity to recruit accessory proteins (e.g. motor proteins) (1)(2)(3) 5). 20 A host of tubulin post-translational modifications (PTMs) have been reported in a range of cell types, including (but not limited 21 to) tyrosination, acetylation, glutamylation, glycylation, and phosphorylation. In recent years links between the loss of specific 22 tubulin PTMs, either through the aberrant expression of tubulin isoforms or the loss of effecting or reversing enzymes, has 23 emerged (5). The loss of post-translationally modified tubulin has been reported to impact motile and non-motile ciliary 24 function (including respiratory cilia, retinal cells), spermatogenesis, muscular disorders, and neurological development and 25 function (1,(5)(6)(7)(8)(9)(10)(11). Of the many cell systems in which careful regulation of tubulin modification is required for healthy function, 26 the role of the tubulin code in the generation of blood platelets from their progenitors, megakaryocytes (MKs) remains relatively 27 poorly understood. 28 Platelets are the smallest component of peripheral blood, and circulate as anucleate cells with ...

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Organization of associating or crosslinked actin filaments in confinement

2019

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A key factor of actin cytoskeleton organization in cells is the interplay between the dynamical properties of actin filaments and cell geometry, which restricts, confines and directs their orientation. Crosslinking interactions among actin filaments, together with geometrical cues and regulatory proteins can give rise to contractile rings in dividing cells and actin rings in neurons. Motivated by recent in vitro experiments, in this work we performed computer simulations to study basic aspects of the interplay between confinement and attractive interactions between actin filaments. We used a spring-bead model and Brownian dynamics to simulate semiflexible actin filaments that polymerize in a confining sphere with a rate proportional to the monomer concentration. We model crosslinking, or attraction through the depletion interaction, implicitly as an attractive short-range potential between filament beads. In confining geometries smaller than the persistence length of actin filaments, we show rings can form by curving of filaments of length comparable to, or longer than the confinement diameter. Rings form for optimal ranges of attractive interactions that exist in between open bundles, irregular loops, aggregated and unbundled morphologies. The probability of ring formation is promoted by attraction to the confining sphere boundary and decreases for large radii and initial monomer concentrations, in agreement with prior experimental data. The model reproduces ring formation along the flat plane of oblate ellipsoids.

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Balance of microtubule stiffness and cortical tension determines the size of blood cells with marginal band across species

Cited by 56 publications

References 45 publications

Cytoskeleton mechanics determine resting size and activation dynamics of platelets

Cytoskeleton mechanics determine resting size and activation dynamics of platelets

Post-translational polymodification of β1 tubulin regulates motor protein localisation in platelet production and function

Organization of associating or crosslinked actin filaments in confinement

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