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Mechanistic Mathematical Modeling of Spatiotemporal Microtubule Dynamics and Regulation in Vivo

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Research Collection Doctoral Thesis Mechanistic mathematical modeling of spatiotemporal microtubule dynamics and regulation in vivo Author(s): Widmer, Lukas A. Publication Date: 2018 Permanent Link: https://doi.org/10.3929/ethz-b-000328562 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library diss. eth no. 25588 MECHANISTICMATHEMATICAL MODELINGOFSPATIOTEMPORAL MICROTUBULEDYNAMICSAND REGULATION INVIVO A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (dr. sc. eth zurich) presented by LUKASANDREASWIDMER msc. eth cbb born on 11. 03. 1987 citizen of luzern and ruswil lu, switzerland accepted on the recommendation of Prof. Dr. Jörg Stelling, examiner Prof. Dr. Yves Barral, co-examiner Prof. Dr. François Nédélec, co-examiner Prof. Dr. Linda Petzold, co-examiner 2018 Lukas Andreas Widmer Mechanistic mathematical modeling of spatiotemporal microtubule dynamics and regulation in vivo © 2018 ACKNOWLEDGEMENTS We are all much more than the sum of our work, and there is a great many whom I would like to thank for their support and encouragement, without which this thesis would not exist. I would like to thank my supervisor, Prof. Jörg Stelling, for giving me the opportunity to conduct my PhD research in his group. Jörg, you have been a great scientific mentor, and the scientific freedom you give your students is something I enjoyed a lot – you made it possible for me to develop my own theories, and put them to the test. I thank you for the trust you put into me, giving me a challenge to rise up to, and for always having an open door, whether in times of excitement or despair. It was a great pleasure to work with my comrades-in-arms on the TubeX project. I thank Xiuzhen Chen and her supervisor Prof. Yves Barral at D-BIOL for teaching me a lot about yeast in general and its microtubule cytoskeleton in particular, their openness in sharing data, intense and stimulating discussions, and keeping an open mind regarding modeling results. I thank Marcel Stangier and Prof. Michel Steinmetz from the Paul Scherrer Institute for providing valuable structural insights on the many proteins interacting to give rise to microtubule dynamics, and stimulating discussions during our meetings. I would also like to thank the former TubeX members Mathias Bayer, Jette Lengefeld and Denis Samuylov for fruitful discussions. My committee members also contributed valuable insights, and I would like to thank Prof. François Nédélec for organizing the EMBO Practical Course on Modeling Cellular Processes in Space and Time, during which I learnt a lot all while having a great time, as well as for stimulating discussions during the bi-annual microtubule symposia at EMBL. I thank Prof. Linda Petzold for valuable discussions regarding coordinate-aware reaction-diffusion master equation models during the BSSE department review. My parents Andreas and Evelyne awoke my curiosity, encouraged me to choose my own path, and their support in my pursuit of science was invaluable – dad, I will always remember your motto: “but where is the data?” Without my siblings Felix, David and Jasmin, the past years would have indeed been much duller, and I am very grateful for the time we get to spend together discussing, playing games, skiing, snowboarding, and traveling – you guys are awesome! I thank the entire current and past Stelling group – Alina, Asli, Andreas, Charlotte, Claude, Diana, Eleni, Ellis, Eve, Fabian, Hans-Michael, Jana, Julia, Kristina, Lekshmi, Mattia, Mikolaj, Moritz, Mikael, Pencho, Robert, Sotiris and Thomas – for discussions, being great colleagues, and all the fun we had during our retreats! I would especially like to thank Moritz for valuable discussions and being a great friend, if it had not been for you, I might not have embarked on this scientific adventure in the first place. Mathias was a great help while getting started. Jana is the best office mate one could wish for, I thank her for all the scientific and emotional support, and I wish her all the best in finishing up her PhD thesis. I would also like to thank Kristina and Andreas for introducing me to yeast lab and microscopy basics, and my master student Alain and project student Natalia for their contributions to modeling the yeast signaling pathways involved in mitosis. iii iv Next, my thanks go to my shared Master student Harun, who performed excellent work on GapMiner, a joint project with Sabine, as well as preparatory work in his lab rotation. I also had the privilege of tutoring our iGEM students of 2013, 2014 and 2015 – you taught me a lot, and I hope I was able to teach you some skills you still find useful as well. I also would like to extend thanks to the ITSC team for keeping our cluster happy and science happening – a special thank you goes to John Ryan and Martin Fox for their excellent support and sharing their sysadmin experience over the last few years – keeping everything running smoothly was not always easy. Having good friends along for the ride during my PhD studies also was of great help – I always enjoyed time with Andreas Ritter, from planning weddings to discussing beer brewing and other non-work-related topics. I also enjoyed a lot of board and card game nights with Lukas Beyeler, Susana Posada Cespedes, and Marek Pikulski – we definitely saved the world from overwhelming epidemics more often than we succumbed to rapidly-mutating strains. I want to thank my better half, Sabine Österle, for her unconditional support through a time that was filled with joy, tears, sweat, and excitement. Doing challenging research together and co-supervising students was a fun experience – it was a privilege to be able to work on a true “in-house” collaboration. Finally, financial support by the Swiss Initiative for Systems Biology (SystemsX.ch, project TubeX) evaluated by the Swiss National Science Foundation is gratefully acknowl- edged. ABSTRACT The microtubule cytoskeleton is a key component of eukaryotic life: during cell division it forms the mitotic spindle, an apparatus that is responsible for faithfully segregating genetic material into the daughter cells. For this purpose, cells form microtubule asters on opposite poles in the spindle – in the budding yeast Saccharomyces cerevisiae these are termed spindle pole bodies (SPBs), the equivalent of the mammalian centrosomes. In this thesis, we are concerned with the basic mechanisms of function of the micro- tubule dynamics that allow for spindle assembly, alignment, and positioning in vivo, using budding yeast as a model organism. We aim to further our mechanistic understanding by mathematically modeling them in space, time, and on the appropriate molecular abun- dance scales: from microscopic representations of chemical reactions up to continuum dynamics. We highlight recent progress in bridging model classes and outline current challenges in such multi-scale models. We then choose a modeling approach with an appropriate resolution to cover stochastic intracellular microtubule dynamics as well as spatiotemporal regulatory networks that modulate microtubule dynamics through microtubule-associated proteins (MAPs) in vivo. We developed a simulation software in C++ that can simulate models of the chosen reaction-diffusion master equation type in conjunction with microtubule dynamics, and apply it to simulate autonucleated microtubules in Xenopus laevis egg extract in conjunction with a stochastic guanosine triphosphate cap model for each microtubule. To form a quantitative basis for our modeling efforts in yeast, we next investigate the abundance and basic polymerization properties of tubulin in vitro and in vivo. Our meta- analysis of data on tubulin abundance in S. cerevisiae and Schizosaccharomyces pombe cells, as well as in their respective spindles, suggests that there is a necessity for microtubule polymerases in vivo due to the low amount of free tubulin. Furthermore, we illustrate that asymmetric microtubule dynamics require regulation beyond controlling tubulin assembly via the global tubulin concentration. Finally, we establish an automated pipeline to analyze manually-annotated traces along microtubules imaged in vivo using fluorescence microscopy. This pipeline allowed us to visualize mean motor density along microtubules of varying lengths on the example of the kinesin motor Kip2. We develop a spatiotemporal stochastic model that describes motor binding and movement on the microtubule, and a fluorescence imaging measurement model corresponding to our in vivo analysis pipeline. Combining the in vivo data from this pipeline, analytical and computational predictions from the stochastic and measurement models, as well as structural information, we conclusively show that Kip2 is predominantly loaded at the SPBs in vivo, acting as a remote control for microtubule plus end dynamics from the SPB at the minus end. This remote control is enabled by preventing Kip2 from binding on the microtubule lattice, a feature that can be disabled by preventing Kip2 from being phosphorylated, and the high processivity and movement speed of the Kip2 motor. Asymmetric Kip2 binding at the two SPBs can thus explain the asymmetry in microtubule length between the microtubules in the mother and the bud v vi during mitosis. This binding depends on the SPB outer plaque component Spc72, and is modulated by phosphorylation by the Polo-like kinase Cdc5. In the future, we envision a spatiotemporal model that integrates the mitotic exit network that Cdc5 (and opposing phosphatases) are a part of, as well as microtubule dynamics at the two SPBs in mother and bud with the associated MAPs – quantitatively capturing our current state of knowledge in silico, helping to discriminate between biological hypotheses and serving as a tool to drive new experiments. ZUSAMMENFASSUNG Das Mikrotubuli-Zytoskelett ist ein grundlegender Bestandteil des eukaryotischen Le- bens: Während der Zellteilung bildet es den mitotischen Spindelapparat, der für die genaue Aufteilung des Erbgutes in die Tochterzellen verantwortlich ist.
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