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      A Polarised Population of Dynamic Microtubules Mediates Homeostatic Length Control in Animal Cells


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          An analysis of cells grown on micro-patterned lines, and of cells during zebrafish development, identifies a population of microtubules that align along the long axis of cells to mediate homeostatic length control.


          Because physical form and function are intimately linked, mechanisms that maintain cell shape and size within strict limits are likely to be important for a wide variety of biological processes. However, while intrinsic controls have been found to contribute to the relatively well-defined shape of bacteria and yeast cells, the extent to which individual cells from a multicellular animal control their plastic form remains unclear. Here, using micropatterned lines to limit cell extension to one dimension, we show that cells spread to a characteristic steady-state length that is independent of cell size, pattern width, and cortical actin. Instead, homeostatic length control on lines depends on a population of dynamic microtubules that lead during cell extension, and that are aligned along the long cell axis as the result of interactions of microtubule plus ends with the lateral cell cortex. Similarly, during the development of the zebrafish neural tube, elongated neuroepithelial cells maintain a relatively well-defined length that is independent of cell size but dependent upon oriented microtubules. A simple, quantitative model of cellular extension driven by microtubules recapitulates cell elongation on lines, the steady-state distribution of microtubules, and cell length homeostasis, and predicts the effects of microtubule inhibitors on cell length. Together this experimental and theoretical analysis suggests that microtubule dynamics impose unexpected limits on cell geometry that enable cells to regulate their length. Since cells are the building blocks and architects of tissue morphogenesis, such intrinsically defined limits may be important for development and homeostasis in multicellular organisms.

          Author Summary

          Because many physical processes change with scale, size control is a fundamental problem for living systems. While in some instances the size of a structure is directly determined by the dimensions of its individual constituents, many biological structures are dynamic, self-organising assemblies of relatively small component parts. How such assemblies are maintained within defined size limits remains poorly understood. Here, by confining cells to spread on lines, we show that animal cells reach a defined length that is independent of their volume and width. In searching for a “ruler” that might determine this axial limit to cell spreading, we identified a population of dynamic microtubule polymers that become oriented along the long axis of cells. This growing population of oriented microtubules drives extension of the spreading cell margin while, conversely, interactions with the cell margin promote microtubule depolymerisation, leading to cell shortening. Using a mathematical model we show that this coupling of dynamic microtubule polymerisation and depolymerisation with directed cell elongation is sufficient to explain the limit to cell spreading and cell length homeostasis. Because microtubules appear to regulate cell length in a similar way in the developing zebrafish neural tube, we suggest that this microtubule-dependent mechanism is likely to be of widespread importance for the regulation of cell and tissue geometry.

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          Most cited references 59

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          Soft lithography in biology and biochemistry.

          Soft lithography, a set of techniques for microfabrication, is based on printing and molding using elastomeric stamps with the patterns of interest in basrelief. As a technique for fabricating microstructures for biological applications, soft lithography overcomes many of the shortcomings of photolithography. In particular, soft lithography offers the ability to control the molecular structure of surfaces and to pattern the complex molecules relevant to biology, to fabricate channel structures appropriate for microfluidics, and to pattern and manipulate cells. For the relatively large feature sizes used in biology (> or = 50 microns), production of prototype patterns and structures is convenient, inexpensive, and rapid. Self-assembled monolayers of alkanethiolates on gold are particularly easy to pattern by soft lithography, and they provide exquisite control over surface biochemistry.
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            Rational design and characterization of a Rac GTPase-specific small molecule inhibitor.

            The signaling pathways mediated by Rho family GTPases have been implicated in many aspects of cell biology. The specificity of the pathways is achieved in part by the selective interaction between Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. Here, we report a first-generation small-molecule inhibitor of Rac GTPase targeting Rac activation by GEF. The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification. In vitro it could effectively inhibit Rac1 binding and activation by the Rac-specific GEF Trio or Tiam1 in a dose-dependent manner without interfering with the closely related Cdc42 or RhoA binding or activation by their respective GEFs or with Rac1 interaction with BcrGAP or effector PAK1. In cells, it potently blocked serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of endogenous Cdc42 or RhoA. Moreover, this compound reduced Trio or Tiam1 but not Vav, Lbc, Intersectin, or a constitutively active Rac1 mutant-stimulated cell growth and suppressed Trio, Tiam1, or Ras-induced cell transformation. When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity. Thus, NSC23766 constitutes a Rac-specific small-molecule inhibitor that could be useful to study the role of Rac in various cellular functions and to reverse tumor cell phenotypes associated with Rac deregulation.
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              Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons.

              Recently, we and others reported that the doublecortin gene is responsible for X-linked lissencephaly and subcortical laminar heterotopia. Here, we show that Doublecortin is expressed in the brain throughout the period of corticogenesis in migrating and differentiating neurons. Immunohistochemical studies show its localization in the soma and leading processes of tangentially migrating neurons, and a strong axonal labeling is observed in differentiating neurons. In cultured neurons, Doublecortin expression is highest in the distal parts of developing processes. We demonstrate by sedimentation and microscopy studies that Doublecortin is associated with microtubules (MTs) and postulate that it is a novel MAP. Our data suggest that the cortical dysgeneses associated with the loss of Doublecortin function might result from abnormal cytoskeletal dynamics in neuronal cell development.

                Author and article information

                Role: Academic Editor
                PLoS Biol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                November 2010
                November 2010
                16 November 2010
                : 8
                : 11
                [1 ]Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, London, United Kingdom
                [2 ]London Centre for Nanotechnology, London, United Kingdom
                [3 ]Department of Medicine, University College London, London, United Kingdom
                [4 ]Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
                [5 ]Medical Research Council Centre for Developmental Neurobiology, King's College London, London, United Kingdom
                University of California, Davis, United States of America
                Author notes

                The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: RP XR JDWC RAM BB. Performed the experiments: RP XR. Analyzed the data: RP XR. Wrote the paper: RP XR BB. Carried out all the zebrafish work: XR. Made the initial observations and developed the methods that led to the current study: KDI. Co-conceived the zebrafish work: JDWC. Co-supervised the cell and micropatterning work: RAM.

                Picone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 17
                Research Article
                Cell Biology
                Cell Biology/Cell Adhesion
                Cell Biology/Cell Growth and Division
                Cell Biology/Cytoskeleton
                Computer Science/Systems and Control Theory

                Life sciences


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