ayout 1 - EMBL Grenoble

Cell Biology and Biophysics UnitCellular architecturePrevious and current researchModern microscopy has shown us the dynamic nature of biological organisation. During cell division,for example, chromosome segregation is accomplished by a structure called a mitotic spindle,made of chromosomes, microtubules (polar filaments) and numerous associated proteins. Allthese elements are connected into a structure which is solid and yet highly dynamic at the sametime: the main components – microtubules – are in rapid turnover. They grow, shrink and disappearin a matter of minutes, while the mitotic spindles can subsist for hours. In fact, none of themicrotubule associated proteins – such as molecular motors – remain for long, yet their permanentstochastic interactions at the molecular level result in a stable overall structure: a spindle conservesits shape and size, and applies precisely the balanced forces necessary to position andsegregate the chromosomes.The spindle is thus a fascinating structure, which illustrates a central question in biology: how canthe uncoordinated and inevitably imperfect actions of proteins and molecules result in a structureable to fulfil its biological function with the utmost accuracy?Obviously, some kind of averaging is going on, but deciphering how multiple elements (proteins)contribute to a system’s properties is not straightforward. It is a challenging problem for many reasons:1) there are many different types of protein implicated; 2) elements are not present in so many copies, such as to allow a simple statisticalaveraging; and 3) most of their interactions are dynamic and sometimes poorly characterised.Within the field of the cytoskeleton, we address these aspects in practical terms, by developing in vitro experiments and modelling tools. Thein vitro approach allows us to reduce the number of components in the system: we can either remove a specific protein, or start from scratchby mixing purified components. Modelling allows us to recapitulate the process of protein organisation in a framework in which all the interactionsare known exactly and can be specified at will. In practice, we develop innovative numerical methods to simulate the collective behaviourof multiple polar fibres and of theirassociated proteins. They are implemented ina simulation called cytosim, which is beingapplied to diverse problems of cytoskeletalorganisation. Simulations are often used tovalidate or refute pre-existing ideas, but theycan also be used in a more creative way: onecan generate systematically various propertiesfor the molecules, and automatically testtheir ability to form stable structures. Theanalysis of successful scenarios leads to theformulation of hypotheses, which can later betested experimentally.Future projects and goalsFrançois NédélecPhD 1998, Université Paris 11.Postdoctoral research atEMBL.BioMS group leader since2002.Joint appointment with theStructural and ComputationalBiology Unit.Simulation of the microtubule cytoskeleton in the fission yeast S. pombe.We will study systems in which experimentsand theory can be synergistically combined.We currently focus on chromosome-microtubule interactions using Xenopus egg extracts, and experimental system in which many parts ofmitosis can be recapitulated. We are generally interested in modelling cellular processes in which the cytoskeleton serves a major role, suchas the different stages of mitosis, the generation of cell shape in S. pombe, and the generation of asymmetry during cell division.Selected referencesAthale, C.A., Dinarina, A., Mora-Coral, M., Pugieux, C., Nédélec, F. &Karsenti, E. (2008). Regulation of Microtubule Dynamics by ReactionCascades Around Chromosomes. Science, 322, 123-127Jékely, G., Colombelli, J., Hausen, H., Guy, K., Stelzer, E., Nédélec,F. & Arendt, D. (2008). Mechanism of phototaxis in marinezooplankton. Nature, 56, 395-399Janson, M.E., Loughlin, R., Loiodice, I., Fu, C., Brunner, D., Nédélec,Fr. & Tran, P.T. (2007). Crosslinkers and motors organize dynamicmicrotubules to form stable bipolar arrays in fission yeast. Cell, 128,357-368Kozlowski, C., Srayko, M. & Nédélec, Fr. (2007). Cortical microtubulecontacts position the spindle in C. elegans embryos. Cell, 129, 99-51017