Régulation de la Dynamique des Microtubules par code Tubuline

Publications de l’équipe

Année de publication : 2018

Renaud Chabrier, Carsten Janke (2018 Mar 1)

The comeback of hand drawing in modern life sciences.

Nature reviews. Molecular cell biology : DOI : 10.1038/nrm.2017.126 En savoir plus
Résumé

Scientific manuscripts are full of images. Since the birth of the life sciences, these images were in a form of hand drawings, with great examples from da Vinci, Hooke, van Leeuwenhoek, Remak, Buffon, Bovery, Darwin, Huxley, Haeckel and Gray’s Anatomy to name a few. However, in the course of the past century, photographs and simplified schematics have gradually taken over as a way of illustrating scientific data and concepts, assuming that these are ‘accurate’ representations of the truth. Here, we argue for the importance of reviving the art of scientific drawings as a way of effectively communicating complex scientific ideas to both specialists and the general public.

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Carla G Silva, Elise Peyre, Mohit H Adhikari, Sylvia Tielens, Sebastian Tanco, Petra Van Damme, Lorenza Magno, Nathalie Krusy, Gulistan Agirman, Maria M Magiera, Nicoletta Kessaris, Brigitte Malgrange, Annie Andrieux, Carsten Janke, Laurent Nguyen (2018 Feb 22)

Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis.

Cell : 1063-1078.e19 : DOI : 10.1016/j.cell.2018.01.031 En savoir plus
Résumé

Interneurons navigate along multiple tangential paths to settle into appropriate cortical layers. They undergo a saltatory migration paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. It remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes post-translational protein deglutamylation, controls the pausing of migrating cortical interneurons. Moreover, we demonstrate that pausing during migration attenuates movement simultaneity at the population level, thereby controlling the flow of interneurons invading the cortex. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also impairs the generation of age-matched projection neurons of the upper layers.

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Carsten Janke (2018 Feb 19)

A unified reviewing format for grant applications and evaluations.

EMBO reports : 187-188 : DOI : 10.15252/embr.201745611 En savoir plus
Résumé

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Rodrigo Muñoz-Castañeda, David Díaz, Leticia Peris, Annie Andrieux, Christophe Bosc, José M Muñoz-Castañeda, Carsten Janke, José R Alonso, Marie-Jo Moutin, Eduardo Weruaga (2018 Feb 15)

Cytoskeleton stability is essential for the integrity of the cerebellum and its motor- and affective-related behaviors.

Scientific reports : 3072 : DOI : 10.1038/s41598-018-21470-2 En savoir plus
Résumé

The cerebellum plays a key role in motor tasks, but its involvement in cognition is still being considered. Although there is an association of different psychiatric and cognitive disorders with cerebellar impairments, the lack of time-course studies has hindered the understanding of the involvement of cerebellum in cognitive and non-motor functions. Such association was here studied using the Purkinje Cell Degeneration mutant mouse, a model of selective and progressive cerebellar degeneration that lacks the cytosolic carboxypeptidase 1 (CCP1). The effects of the absence of this enzyme on the cerebellum of mutant mice were analyzed both in vitro and in vivo. These analyses were carried out longitudinally (throughout both the pre-neurodegenerative and neurodegenerative stages) and different motor and non-motor tests were performed. We demonstrate that the lack of CCP1 affects microtubule dynamics and flexibility, defects that contribute to the morphological alterations of the Purkinje cells (PCs), and to progressive cerebellar breakdown. Moreover, this degeneration led not only to motor defects but also to gradual cognitive impairments, directly related to the progression of cellular damage. Our findings confirm the cerebellar implication in non-motor tasks, where the formation of the healthy, typical PCs structure is necessary for normal cognitive and affective behavior.

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Année de publication : 2017

Carsten Janke, Guillaume Montagnac (2017 Dec 4)

Causes and Consequences of Microtubule Acetylation.

Current biology : CB : R1287-R1292 : DOI : S0960-9822(17)31381-7 En savoir plus
Résumé

Among the different types of cytoskeletal components, microtubules arguably accumulate the greatest diversity of post-translational modifications (PTMs). Acetylation of lysine 40 (K40) of α-tubulin has received particular attention because it is the only tubulin PTM to be found in the lumen of microtubules: most other tubulin PTMs are found at the outer surface of the microtubule. As a consequence, the enzyme catalyzing K40 acetylation needs to penetrate the narrow microtubule lumen to find its substrate. Acetylated microtubules have been considered to be stable, long-lived microtubules; however, until recently, there was little information about whether the longevity of these microtubules is the cause or the consequence of acetylation. Current advances suggest that this PTM helps the microtubule lattice to cope with mechanical stress, thus facilitating microtubule self-repair. These observations now shed new light on the structural integrity of microtubules, as well as on the mechanisms and biological functions of tubulin acetylation. Here, we discuss recent insights into how acetylation is generated in the lumen of microtubules, and how this ‘hidden’ PTM can control the properties and functions of microtubules.

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Takashi Akera, Lukáš Chmátal, Emily Trimm, Karren Yang, Chanat Aonbangkhen, David M Chenoweth, Carsten Janke, Richard M Schultz, Michael A Lampson (2017 Nov 3)

Spindle asymmetry drives non-Mendelian chromosome segregation.

Science (New York, N.Y.) : 668-672 : DOI : 10.1126/science.aan0092 En savoir plus
Résumé

Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.

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Sudarshan Gadadhar, Hala Dadi, Satish Bodakuntla, Anne Schnitzler, Ivan Bièche, Filippo Rusconi, Carsten Janke (2017 Sep 4)

Tubulin glycylation controls primary cilia length.

The Journal of cell biology : 2701-2713 : DOI : 10.1083/jcb.201612050 En savoir plus
Résumé

As essential components of the eukaryotic cytoskeleton, microtubules fulfill a variety of functions that can be temporally and spatially controlled by tubulin posttranslational modifications. Tubulin glycylation has so far been mostly found on motile cilia and flagella, where it is involved in the stabilization of the axoneme. In contrast, barely anything is known about the role of glycylation in primary cilia because of limitations in detecting this modification in these organelles. We thus developed novel glycylation-specific antibodies with which we detected glycylation in many primary cilia. Glycylation accumulates in primary cilia in a length-dependent manner, and depletion or overexpression of glycylating enzymes modulates the length of primary cilia in cultured cells. This strongly suggests that glycylation is essential for the homeostasis of primary cilia, which has important implications for human disorders related to primary cilia dysfunctions, such as ciliopathies and certain types of cancer.

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Richard Belvindrah, Kathiresan Natarajan, Preety Shabajee, Elodie Bruel-Jungerman, Jennifer Bernard, Marie Goutierre, Imane Moutkine, Xavier H Jaglin, Mythili Savariradjane, Theano Irinopoulou, Jean-Christophe Poncer, Carsten Janke, Fiona Francis (2017 Aug 7)

Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration.

The Journal of cell biology : 2443-2461 : DOI : 10.1083/jcb.201607074 En savoir plus
Résumé

Brain development involves extensive migration of neurons. Microtubules (MTs) are key cellular effectors of neuronal displacement that are assembled from α/β-tubulin heterodimers. Mutation of the α-tubulin isotype TUBA1A is associated with cortical malformations in humans. In this study, we provide detailed in vivo and in vitro analyses of Tuba1a mutants. In mice carrying a Tuba1a missense mutation (S140G), neurons accumulate, and glial cells are dispersed along the rostral migratory stream in postnatal and adult brains. Live imaging of Tuba1a-mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus-centrosome (N-C) coupling. Tuba1a mutation led to increased straightness of newly polymerized MTs, and structural modeling data suggest a conformational change in the α/β-tubulin heterodimer. We show that Tuba8, another α-tubulin isotype previously associated with cortical malformations, has altered function compared with Tuba1a. Our work shows that Tuba1a plays an essential, noncompensated role in neuronal saltatory migration in vivo and highlights the importance of MT flexibility in N-C coupling and neuronal-branching regulation during neuronal migration.

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Kathiresan Natarajan, Sudarshan Gadadhar, Judith Souphron, Maria M Magiera, Carsten Janke (2017 Jun 1)

Molecular interactions between tubulin tails and glutamylases reveal determinants of glutamylation patterns.

EMBO reports : 1013-1026 : DOI : 10.15252/embr.201643751 En savoir plus
Résumé

Posttranslational modifications of tubulin currently emerge as key regulators of microtubule functions. Polyglutamylation generates a variety of modification patterns that are essential for controlling microtubule functions in different cell types and organelles, and deregulation of these patterns has been linked to ciliopathies, cancer and neurodegeneration. How the different glutamylating enzymes determine precise modification patterns has so far remained elusive. Using computational modelling, molecular dynamics simulations and mutational analyses we now show how the carboxy-terminal tails of tubulin bind into the active sites of glutamylases. Our models suggest that the glutamylation sites on α- and β-tubulins are determined by the positioning of the tails within the catalytic pocket. Moreover, we found that the binding modes of α- and β-tubulin tails are highly similar, implying that most enzymes could potentially modify both, α- and β-tubulin. This supports a model in which the binding of the enzymes to the entire microtubule lattice, but not the specificity of the C-terminal tubulin tails to their active sites, determines the catalytic specificities of glutamylases.

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Sudarshan Gadadhar, Satish Bodakuntla, Kathiresan Natarajan, Carsten Janke (2017 Apr 15)

The tubulin code at a glance.

Journal of cell science : 1347-1353 : DOI : 10.1242/jcs.199471 En savoir plus
Résumé

Microtubules are key cytoskeletal elements of all eukaryotic cells and are assembled of evolutionarily conserved α-tubulin-β-tubulin heterodimers. Despite their uniform structure, microtubules fulfill a large diversity of functions. A regulatory mechanism to control the specialization of the microtubule cytoskeleton is the ‘tubulin code’, which is generated by (i) expression of different α- and β-tubulin isotypes, and by (ii) post-translational modifications of tubulin. In this Cell Science at a Glance article and the accompanying poster, we provide a comprehensive overview of the molecular components of the tubulin code, and discuss the mechanisms by which these components contribute to the generation of functionally specialized microtubules.

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Akendengue L., Trepout S., Grana M., Voegele A., Janke C., Raynal B., Chenal A., Marco S., Wehenkel A.M. (2017 Mar 30)

Bacterial kinesin light chain (Bklc) links the Btub cytoskeleton to membranes

Scientific Reports : 7 : 45668 : DOI : 10.1038/srep45668 En savoir plus
Résumé

Bacterial kinesin light chain is a TPR domain-containing protein encoded by the bklc gene, which co-localizes with the bacterial tubulin (btub) genes in a conserved operon in Prosthecobacter. Btub heterodimers show high structural homology with eukaryotic tubulin and assemble into head-to-tail protofilaments. Intriguingly, Bklc is homologous to the light chain of the microtubule motor kinesin and could thus represent an additional eukaryotic-like cytoskeletal element in bacteria. Using biochemical characterization as well as cryo-electron tomography we show here that Bklc interacts specifically with Btub protofilaments, as well as lipid vesicles and could thus play a role in anchoring the Btub filaments to the membrane protrusions in Prosthecobacter where they specifically localize in vivo. This work sheds new light into possible ways in which the microtubule cytoskeleton may have evolved linking precursors of microtubules to the membrane via the kinesin moiety that in today’s eukaryotic cytoskeleton links vesicle-packaged cargo to microtubules.

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Montserrat Bosch Grau, Christel Masson, Sudarshan Gadadhar, Cecilia Rocha, Olivia Tort, Patricia Marques Sousa, Sophie Vacher, Ivan Bieche, Carsten Janke (2017 Mar 1)

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration.

Journal of cell science : DOI : 10.1242/jcs.199091 En savoir plus
Résumé

Tubulin is subject to a wide variety of posttranslational modifications, which as part of the tubulin code are involved in the regulation of microtubule functions. Glycylation has so far predominantly been found in motile cilia and flagella, and absence of this modification leads to ciliary disassembly. Here we demonstrate that the connecting cilia of photoreceptors, which are non-motile sensory cilia, are also dependent on glycylation. In contrast to many other tissues, only one glycylase, TTLL3, is expressed in retina. Ttll3(-/-) mice lack glycylation in photoreceptors, which results in shortening of connecting cilia and slow retinal degeneration. Moreover, absence of glycylation results in increased levels of tubulin glutamylation in photoreceptors, and inversely, hyperglutamylation in the pcd mouse abolishes glycylation. This suggests that both posttranslational modifications compete for modification sites, and that unbalancing the glutamylation/glycylation equilibrium on axonemes of connecting cilia, notwithstanding by which enzymatic mechanism, invariably leads to retinal degeneration.

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Année de publication : 2016

Nathalie Ly, Nadia Elkhatib, Enzo Bresteau, Olivier Piétrement, Mehdi Khaled, Maria M Magiera, Carsten Janke, Eric Le Cam, Andrew D Rutenberg, Guillaume Montagnac (2016 Oct 18)

αTAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities.

Scientific reports : 35624 : DOI : 10.1038/srep35624 En savoir plus
Résumé

Acetylation of the lysine 40 of α-tubulin (K40) is a post-translational modification occurring in the lumen of microtubules (MTs) and is controlled by the α-tubulin acetyl-transferase αTAT1. How αTAT1 accesses the lumen and acetylates α-tubulin there has been an open question. Here, we report that acetylation starts at open ends of MTs and progressively spreads longitudinally from there. We observed acetylation marks at the open ends of in vivo MTs re-growing after a Nocodazole block, and acetylated segments growing in length with time. Bias for MTs extremities was even more pronounced when using non-dynamic MTs extracted from HeLa cells. In contrast, K40 acetylation was mostly uniform along the length of MTs reconstituted from purified tubulin in vitro. Quantitative modelling of luminal diffusion of αTAT1 suggested that the uniform acetylation pattern observed in vitro is consistent with defects in the MT lattice providing lateral access to the lumen. Indeed, we observed that in vitro MTs are permeable to macromolecules along their shaft while cellular MTs are not. Our results demonstrate αTAT1 enters the lumen from open extremities and spreads K40 acetylation marks longitudinally along cellular MTs. This mode of tip-directed microtubule acetylation may allow for selective acetylation of subsets of microtubules.

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Soumyananda Chakraborti, Kathiresan Natarajan, Julian Curiel, Carsten Janke, Judy Liu (2016 Oct 1)

The emerging role of the tubulin code: From the tubulin molecule to neuronal function and disease.

Cytoskeleton (Hoboken, N.J.) : DOI : 10.1002/cm.21290 En savoir plus
Résumé

Across different cell types and tissues, microtubules are assembled from highly conserved dimers of α- and β-tubulin. Despite their highly similar structures, microtubules have functional heterogeneity, generated either by the expression of different tubulin genes, encoding distinct isotypes, or by post-translational modifications of tubulin. This genetically encoded and post-translationally generated heterogeneity of tubulin – the ‘tubulin code’ – has the potential to modulate microtubule structure, dynamics, and interactions with associated proteins. The tubulin code is therefore believed to regulate microtubule functions on a cellular and sub-cellular level. This review highlights the importance of the tubulin code for tubulin structure, as well as on microtubule dynamics and functions in neurons. It further summarizes recent developments in the understanding of mutations in tubulin genes, and how they are linked to neurodegenerative and neurodevelopmental disorders. The current advances in the knowledge of the tubulin code on the molecular and the functional level will certainly lead to a better understanding of how complex signaling events control microtubule functions, especially in cells of the nervous system. This article is protected by copyright. All rights reserved.

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Gary Borisy, Rebecca Heald, Jonathon Howard, Carsten Janke, Andrea Musacchio, Eva Nogales (2016 Apr 22)

Microtubules: 50 years on from the discovery of tubulin.

Nature reviews. Molecular cell biology : 322-8 : DOI : 10.1038/nrm.2016.45 En savoir plus
Résumé

Next year will be the 50th anniversary of the discovery of tubulin. To celebrate this discovery, six leaders in the field of microtubule research reflect on key findings and technological breakthroughs over the past five decades, discuss implications for therapeutic applications and provide their thoughts on what questions need to be addressed in the near future.

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