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      Microtubule stabilization drives 3D centrosome migration to initiate primary ciliogenesis

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          Abstract

          The classical view of centrosome decentering and migration to the cell periphery during ciliogenesis is that it is pulled toward its final destination. Here, Pitaval et al. argue that microtubule stabilization in the early stages of ciliogenesis generates pushing forces that propel the centrosome toward the apical pole.

          Abstract

          Primary cilia are sensory organelles located at the cell surface. Their assembly is primed by centrosome migration to the apical surface, yet surprisingly little is known about this initiating step. To gain insight into the mechanisms driving centrosome migration, we exploited the reproducibility of cell architecture on adhesive micropatterns to investigate the cytoskeletal remodeling supporting it. Microtubule network densification and bundling, with the transient formation of an array of cold-stable microtubules, and actin cytoskeleton asymmetrical contraction participate in concert to drive apical centrosome migration. The distal appendage protein Cep164 appears to be a key actor involved in the cytoskeleton remodeling and centrosome migration, whereas intraflagellar transport 88’s role seems to be restricted to axoneme elongation. Together, our data elucidate the hitherto unexplored mechanism of centrosome migration and show that it is driven by the increase and clustering of mechanical forces to push the centrosome toward the cell apical pole.

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          Most cited references 55

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          Centrioles, centrosomes, and cilia in health and disease.

          Centrioles are barrel-shaped structures that are essential for the formation of centrosomes, cilia, and flagella. Here we review recent advances in our understanding of the function and biogenesis of these organelles, and we emphasize their connection to human disease. Deregulation of centrosome numbers has long been proposed to contribute to genome instability and tumor formation, whereas mutations in centrosomal proteins have recently been genetically linked to microcephaly and dwarfism. Finally, structural or functional centriole aberrations contribute to ciliopathies, a variety of complex diseases that stem from the absence or dysfunction of cilia.
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            Cep164, a novel centriole appendage protein required for primary cilium formation

            Primary cilia (PC) function as microtubule-based sensory antennae projecting from the surface of many eukaryotic cells. They play important roles in mechano- and chemosensory perception and their dysfunction is implicated in developmental disorders and severe diseases. The basal body that functions in PC assembly is derived from the mature centriole, a component of the centrosome. Through a small interfering RNA screen we found several centrosomal proteins (Ceps) to be involved in PC formation. One newly identified protein, Cep164, was indispensable for PC formation and hence characterized in detail. By immunogold electron microscopy, Cep164 could be localized to the distal appendages of mature centrioles. In contrast to ninein and Cep170, two components of subdistal appendages, Cep164 persisted at centrioles throughout mitosis. Moreover, the localizations of Cep164 and ninein/Cep170 were mutually independent during interphase. These data implicate distal appendages in PC formation and identify Cep164 as an excellent marker for these structures.
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              A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly.

              NuMA is a nuclear protein during interphase but redistributes to the spindle poles early in mitosis. To investigate its role during spindle formation, we tested spindle assembly in frog egg extracts from which NuMA was immunodepleted. Immunodepletion revealed that NuMA forms a complex with cytoplasmic dynein and dynactin. The depleted extracts failed to assemble normal mitotic spindles, producing, instead, chromatin-associated irregular arrays of microtubules lacking characteristic spindle poles. A subdomain of the NuMA tail was shown to induce microtubule aster formation by mediating microtubule bundling. Our findings suggest that NuMA forms bifunctional complexes with cytoplasmic dynein and dynactin that can tether microtubules at the spindle poles and that are essential for mitotic spindle pole assembly and stabilization.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                06 November 2017
                : 216
                : 11
                : 3713-3728
                Affiliations
                [1 ]UMR_S 1038, Biomics Lab, University Grenoble-Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut National de la Santé et de la Recherche, Institut de Biosciences et Biotechnologies de Grenoble, Grenoble, France
                [2 ]UMR 5168, CytoMorpho Lab, University Grenoble-Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique, Institut de Biosciences et Biotechnologies de Grenoble, Grenoble, France
                [3 ]UMR_S 1036, Biologie du Cancer et de l'Infection, University Grenoble-Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut National de la Santé et de la Recherche, Institut de Biosciences et Biotechnologies de Grenoble, Grenoble, France
                [4 ]UMRS 1160, CytoMorpho Lab, University Paris Diderot, Institut National de la Santé et de la Recherche, Hôpital Saint Louis, Institut Universitaire d’Hematologie, Paris, France
                Author notes
                Correspondence to Manuel Théry: manuel.thery@ 123456cea.fr ;
                James Sillibourne: sillibou@ 123456gmail.com

                J. Sillibourne’s present address is Autolus Limited, London, England, UK.

                Article
                201610039
                10.1083/jcb.201610039
                5674878
                28993469
                © 2017 Pitaval et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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                Funding
                Funded by: European Research Council, DOI http://dx.doi.org/10.13039/100010663;
                Award ID: SpiCy 310472
                Categories
                Research Articles
                Article
                25
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                Cell biology

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