Exploring cytoskeletal mechanisms at all scales of life — from molecules to organisms/ Exploration des mécanismes du cytosquelette à toutes les échelles de la vie — des molécules aux organismes
Seminar organized by Carsten Janke, Eva Nogales and Filippo Del Bene from September 23 to 28, 2024
Participants
Anna AKHMANOVA (Utrecht University – Utrecht, Pays-Bas), Francesca BARTOLINI (Columbia University – New York , États-Unis), Kim BAUMANN (Springer Nature, Nature Reviews Molecular Cell Biology – London, Royaume-Uni), Satish BODAKUNTLA (National Heart Lung and Blood Institute, NIH, Bethesda, Maryland, États-Unis), Filippo DEL BENE (Institut de la Vision/INSERM, Paris, France), Virginie HAMEL (University of Geneva – Geneva, Suisse), Carsten JANKE (Institut Curie, Pris, France), Zdenek LANSKY (Institute of Biotechnology, Czech Academy of Sciences – Vestec, République Tchèque), Timothy MITCHISON (Harvard Medical School – Boston, MA, États-Unis), Thomas MÜLLER-REICHERT (Technische Universität Dresden – Dresden, Allemagne), François NEDELEC (Cambridge University – Cambridge, Royaume-Uni), Eva NOGALES (UC Berkeley – Berkeley, États-Unis), Gaia PIGINO (Human Technopole – Milan, Italie), Antonina ROLL-MECAK (National Institutes of Health – Bethesda, Maryland, États-Unis), Giampetro SCHIAVO (UCL Queen Square Institute of Neurology – London, Royaume-Uni), Thomas SURREY (Centre for Genomic Information (CRG) – Barcelona, Espagne).
Résumé
Du 23 au 28 septembre 2024, 16 scientifiques, dont un jeune chercheur, et un éditeur scientifique se sont réunis à la Fondation des Treilles pour discuter des orientations futures de la recherche sur le cytosquelette des microtubules. Ces chercheurs étudient une variété de systèmes impliquant les microtubules à différentes échelles, avec différentes approches et méthodes. Tous ces chercheurs partagent le désir d’échanger pour faire progresser l’état actuel des connaissances. Ils représentent un éventail de disciplines qui n’ont généralement pas l’occasion d’interagir étroitement : des biologistes spécialisés dans la biologie cellulaire, la biologie du développement, la biologie des organismes et la médecine, ainsi que des biologistes structuraux et des biophysiciens. Cette diversité s’est reflétée dans les discussions, qui ont montré comment les connaissances moléculaires et structurelles du cytosquelette des microtubules peuvent aider à comprendre les processus physiologiques à plus grande échelle, tels que le développement et la connectivité des neurones, la division cellulaire, le battement des flagelles et la motilité des cellules dans un organisme sain ou malade. En résumé, cette rencontre interdisciplinaire unique fût extrêmement productive et a donné lieu à des discussions approfondies, rendues possibles grâce à l’environnement unique des Treilles et au format flexible de la réunion. Fait remarquable, nous avons commencé à rédiger un article dans lequel nous exposerons notre point de vue consensuel sur les orientations futures du domaine.
Abstract
From September 23rd to 28th, 2024, 15 scientists, including a young researcher (Satish Bodakuntla), and one scientific editor met at the Fondation des Treilles to discuss the future directions of research on the microtubule cytoskeleton. This seminar brought together experts who investigate the regulation of the microtubule cytoskeleton at different scales, in a variety of model systems, and with different approaches and methods, all of whom share a desire to challenge the current state of the art.
The invited scientists represented a wide spectrum of disciplines that would not commonly come together: biologists with backgrounds in cellular, developmental and organism biology, as well as structural biologists and biophysicists whose work focuses on the regulation of the microtubule cytoskeleton. This diversity was reflected in the discussion, which explored how basic molecular and structural knowledge of the microtubule cytoskeleton can help understanding physiological processes that take place on a larger scale, such as neuronal development and connectivity, cell division, flagellar beating and cell motility in health and disease conditions.
Our unique interdisciplinary encounter, which was immensely productive and fostered in-depth discussions, was made possible thanks to the unique environment of Les Treilles and the flexible format of the meeting. Most remarkably, we started to write an opinion article in which we will lay out our consensus view on the global future directions of the field.
Report
Despite overall progress, our understanding of how the microtubule cytoskeleton functions and is regulated at different scales has been a challenging objective that remains unmet. This knowledge gap likely persists because regulatory events at the molecular scale, such as the posttranslational modifications of tubulin, have often important but subtle effects. The intuitive idea that a ‘tubulin code’ could induce subtle biochemical differences that become important at the functional level was first formulated in 1976 in an article by Fulton and Simpson (in Cell Motility, R. Goldman, T. D. Pollard, J. L. Rosenbaum, Eds.), but was never entirely proven. How to tackle this question was one of the aspects discussed in this seminar.
Our seminar took place in a creative and interdisciplinary work atmosphere. Synergizing our complementary expertise, we discussed the regulation and function of the microtubule cytoskeleton from the molecular to the whole-organism level, exploring structural aspects, dynamics of single molecules, collective molecular behaviour, roles in differentiated cells, and the impact on cellular and organismal homeostasis.
To allow this diverse group of scientists to have plenty of opportunities for exchanging novel ideas, we organised this seminar to be highly interactive. The seminar started with a short session of flash talks to allow each participant to introduce themselves. The scientific sessions consisted of short presentations by each participant followed by extended discussions, which often continued during coffee breaks, lunch/dinner and walks through the beautiful estate of Les Treilles.
Anna Akhmanova (University of Utrecht) presented her work on the impact of microtubule-associated proteins that bind at plus ends of ciliary and centriolar microtubules to regulate growth rates, followed by Zdenek Lansky (Czech Academy of Sciences) who described how ATP concentration affects the interaction of microtubules with some of their associated factors. Satish Bodakuntla (postdoctoral researcher at the National Institutes of Health, Bethesda) talked about how he uses cryo-electron tomography (cryo-ET) to reveal the role of microtubule assemblies in facilitating axonal regeneration in central nervous system neurons. Gaia Pigino (Human Technopole Milano) discussed her use of cryo-ET to uncover the atomic details of intraflagellar transport trains, explaining how they reorganize to alter direction and cargo. She further demonstrated how she visualized tubulin post-translational modifications within the axoneme. Thomas Müller-Reichert (University of Technology, Dresden) presented the development of a unique electron tomography approach for large-scale three-dimensional (3D) reconstruction to visualise the ultrastructure of entire mitotic spindles, which now allows us to see each single microtubule in these complex structures. Eva Nogales (HHMI, University of California at Berkeley) showed how to solve atomic structures of microtubules that are bound to multiple associated proteins simultaneously to reveal their unique interplay. Virginie Hamel (University of Geneva) presented her use of expansion microscopy to observe the organization of microtubule interacting factors that result in the unique organization of microtubules in centrioles using light microscopy. Giampietro Schiavo (University College London) studies axonal transport in near-physiological conditions in the nerves of mice and showed how human neurodegenerative disorders, in particular peripheral neuropathies, can be studied in this unique model system. Francesca Bartolini (Columbia University, New York) talked about her studies unveiling the role of microtubule regulation, in particular by a tubulin posttranslational modification, in the aetiology of an inherited form of neuropathic disease. Filippo del Bene (Institut de la Vision Paris) studies the mechanisms underlying cargo transport at the organism level using Zebrafish. He presented impressive examples of how he deciphered the mechanisms of human pathogenic mutations using this fish model. Francois Nédélec (University of Cambridge) uses advanced modelling approaches to develop theories of how cytoskeletal components self-assemble into functional structures. He gave us a live demonstration of the formation of a spindle-like array with a minimum set of components. Thomas Surrey (Centre for Genomic Regulation Barcelona) reconstitutes microtubule assemblies in cell-free systems. He summarised how he used recombinant tubulin with point mutations to determine the molecular mechanisms underlying the formation of the GTP-cap at growing microtubule ends. Antonina Roll-Mecak (National Institutes of Health, Bethesda) presented cryo-EM and X-ray crystallography work describing in atomic detail the way enzymes that add and remove polyglutamate modifications on microtubules can recognize their substrates and cooperate to write the tubulin code. Carsten Janke(Institut Curie Orsay) described how different enzymes regulate the levels of polyglutamylation in the nervous system, and how specific perturbations lead to neurodegeneration. Tim Mitchison (Harvard Medical School Boston) presented proteomic approaches that provide a novel understanding of microtubule organization in cells and showed how mitotic spindles exclude certain cellular components, discussing the implications in cellular self-organisation.
Finally, Kim Baumann (Chief Editor Nature Reviews Molecular Cell Biology) opened the discussion of our common project to write an opinion paper presenting a consensus view on the future directions of the microtubule field. The last day of the seminar was dedicated to the writing of this paper. We worked in small groups, and by the end of the day assembled a draft of a manuscript that will be soon completed.
In summary, our encounter at Les Treilles provided a unique opportunity for us to share our most recent research and discuss novel directions that should allow for transformational advances in the understanding of how fine-tuning the microtubule cytoskeleton at the molecular scale can control cellular and organismal homeostasis. We also discussed the relevance of microtubule research for human health, as more and more studies indicate a direct link between dysfunctions of the microtubule cytoskeleton and human disease. Advancing the understanding of how microtubule functions are regulated, from atomic details to systems-wide functions, promise to substantially change our perception of the cytoskeleton’s role in human disease, potentially leading to new treatments and prevention strategies.
OpenEdition vous propose de citer ce billet de la manière suivante :
ldiebold (11 octobre 2024). Exploring cytoskeletal mechanisms at all scales of life — from molecules to organisms/ Exploration des mécanismes du cytosquelette à toutes les échelles de la vie — des molécules aux organismes. Les carnets de la Fondation des Treilles. Consulté le 18 février 2025 à l’adresse https://doi.org/10.58079/12gd0