The quantitative investigation of how networks of microtubules contract can boost our understanding of actin biology

Belmonte, Julio M

Nédélec, François

English

PubMed

Apollo (Cambridge)

CYTOSKELETONLarge-scale microtubulenetworks contract quite wellThe quantitative investigation of how networks of microtubules contractcan boost our understanding of actin biology.JULIO M BELMONTE AND FRANC¸OIS NE´DE´LECThe cytoskeleton of a cell plays manyimportant roles, such as giving the cell itsshape and organizing its contents. The fil-aments that make up the cytoskeleton assemblefrom protein monomers found in the cell’s cyto-plasm. Two particularly important filament typesfor eukaryotic cells are actin filaments and micro-tubules, which both have crucial roles during vari-ous stages of cell division. For example, themitotic spindle, which is essential for chromo-some segregation, is made of microtubules.Motor proteins (for example myosin, kinesin anddynein) often work with these filaments to trans-port material across the cell and to form contract-ing structures such as muscles.In the past decades, much effort has goneinto characterizing the properties of microtu-bules, actin filaments and motor proteins, andtheir most important properties have probablybeen discovered already. However, we need amuch better understanding of how all thesecomponents work together. Now, in eLife, PeterFoster, Sebastian Fu¨rthauer, Michael Shelley andDaniel Needleman report the first quantitativestudy of an important process in this field ofresearch – the contraction of microtubule net-works (Foster et al., 2015).Instead of relying on purified proteins to studyhow microtubules and motors organize (see, forexample, Hentrich and Surrey, 2010), Fosteret al. used extracts from frog eggs. These pro-vide a more natural mixture of components andare commonly used to study the assembly ofspindles (Sawin and Mitchison, 1991). They alsoperformed the experiments in millimeter-widechannels, allowing them to finely control theoverall geometry of the network. In all the experi-ments, drugs were used to promote the forma-tion of stable microtubules and to prevent actinmonomers assembling into filaments.The microtubules initially formed in randomconfigurations, and under the action of motor pro-teins assembled into star-shaped structures calledasters, as previously reported (Hentrich and Sur-rey, 2010). The whole microtubule network thenslowly contracted.To clarify how these processes occurred, Fos-ter and colleagues – who are based at HarvardUniversity and New York University – used drugsto separately inhibit the activity of kinesin anddynein. This demonstrated that dynein accountsfor 96% of the active stress in microtubule net-works. Remarkably, carefully analyzing the con-traction of the microtubule network alsoprovided insights into actin biology. How is thispossible?Copyright Belmonte and Ne´de´lec.This article is distributed under theterms of the Creative CommonsAttribution License, which permitsunrestricted use and redistributionprovided that the original author andsource are credited.Related research article Foster P, Fu¨rthauerS, Shelley M, Needleman D. 2015. Active con-traction of microtubule networks. eLife 4:e10837. doi: 10.7554/eLife.10837Image Stabilized microtubules organize intonetworks of star-shaped structures calledastersBelmonte and Ne´de´lec. eLife 2016;5:e14076. DOI: 10.7554/eLife.14076 1 of 3INSIGHTWhile microtubule and the actin cytoskeletonare similar in many ways, there are important dif-ferences in the structures they form and thebehaviors they display in vivo. Microtubules tendto form structures such as radial arrays becausethe filaments are few and tend to be straightdue to their high rigidity. Moreover, since micro-tubules are often as long as the cell, the cell sim-ply does not provide enough space to build thelarge microtubule networks that would be nec-essary for observing contraction. On the otherhand, contraction is a common feature of actinnetworks, which can be made of many relativelyshort filaments that are 200 times more flexiblethan microtubules. These considerations reflectthe fact that the behavior of a network is oftenlargely a matter of scale: indeed, networks of fil-aments are usually analyzed in terms of filamentlength, the density of the filaments, and theoverall size of the network (Lenz et al., 2012).In the past, researchers have studied the con-traction of actin networks at the micrometerscale. Now, Foster et al. were able to monitorthe contraction of microtubule networks in milli-meter-wide channels. Looking at the contractilebehavior of filament networks in differentregimes is especially valuable, because differentcontraction mechanisms are thought to operateat different scales. Actin network contractility isthought to require the bending of filaments,whereas microtubule contractility would rely onmolecular motors holding tight to the ends ofthe microtubules (Figure 1). The ability to com-pare these two systems should improve ourunderstanding of the general principles of con-tractility, and thus contribute to actin biology.Foster et al.’s approach may also teach usmore about how mitotic spindles form. Themolecular motor dynein, which induces the bulkcontraction of large random networks, is alsothought to help form the focused poles of thespindle. Specifically, contractions driven bydynein motors likely help the spindle to adoptthe correct shape. Thus by carefully quantifyingthis contraction process, Foster et al. have likelygiven us some of the parameters needed to cre-ate accurate models of the mitotic spindle. Forinstance, the extract always contracted to thesame final density, which is surprisingly similar tothe density of the mitotic spindle. Futureresearch could investigate the mechanismresponsible for this density limit.A remarkable aspect of the study is that Fosteret al. could fit the bulk properties of theFigure 1. Two mechanisms for contraction: buckling and end clustering. Top: When two anti-parallel actinfilaments are bridged by a myosin motor (blue) and a crosslink (green), their relative movement forces onefilament to buckle, resulting in the contraction of the network. Bottom: Microtubule contraction seems to dependon the affinity of dynein motors (red) for the ends of the filaments. For a recent review on the topic of contraction,see Clark et al., 2014.Belmonte and Ne´de´lec. eLife 2016;5:e14076. DOI: 10.7554/eLife.14076 2 of 3Insight Cytoskeleton Large-scale microtubule networks contract quite wellcontraction with a simple active gel theory, usingjust four parameters. For example, the theory canexplain how the microtubule density varies at theedge of the network and how the rate of contrac-tion depends on the overall size of the network.This advance in our knowledge of cytoskeletalnetwork contractility was only possible through atight interplay between experiments and theory.Julio M Belmonte is in the Cell Biology and BiophysicsUnit, European Molecular Biology Laboratory,Heidelberg, GermanyFranc¸ois Ne´de´lec is in the Cell Biology and BiophysicsUnit, European Molecular Biology Laboratory,Heidelberg, Germanynedelec@embl.deCompeting interests: The author declares that nocompeting interests exist.Published 12 February 2016ReferencesClark AG, Wartlick O, Salbreux G, Paluch EK. 2014.Stresses at the cell surface during animal cellmorphogenesis. Current Biology 24:R484–R494. doi:10.1016/j.cub.2014.03.059Foster P, Fu¨rthauer S, Shelley M, Needleman D. 2015.Active contraction of microtubule networks. eLife 4:e10837. doi: 10.7554/eLife.10837Hentrich C, Surrey T. 2010. Microtubule organizationby the antagonistic mitotic motors kinesin-5 andkinesin-14. Journal of Cell Biology 189:465–480. doi:10.1083/jcb.200910125Lenz M, Thoresen T, Gardel M, Dinner A. 2012.Contractile units in disordered actomyosin bundlesarise from F-actin buckling. Physical Review Letters108:238107. doi: 10.1103/PhysRevLett.108.238107Sawin KE, Mitchison TJ. 1991. Mitotic spindleassembly by two different pathways in vitro. Journal ofCell Biology 112:925–940. doi: 10.1083/jcb.112.5.925Belmonte and Ne´de´lec. eLife 2016;5:e14076. DOI: 10.7554/eLife.14076 3 of 3Insight Cytoskeleton Large-scale microtubule networks contract quite well

Large-scale microtubule networks contract quite well.

https://www.repository.cam.ac.uk/bitstream/1810/308553/1/Large-scale%20microtubule%20networks%20contract%20quite%20well.pdf

Large-scale microtubule networks contract quite well.

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