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Microtubules: 50 Years on from the Discovery of Tubulin

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Microtubules: 50 Years on from the Discovery of Tubulin PERSPECTIVES microtubule dynamics and organization VIEWPOINT emerge from a defined set of proteins Microtubules: 50 years on from through reconstitution experiments. Jonathon Howard. One of the big questions back when I got into the microtubule the discovery of tubulin business, around 1990, was how motor proteins such as kinesin and dynein use Gary Borisy, Rebecca Heald, Jonathon Howard, Carsten Janke, ATP hydrolysis to generate force for Andrea Musacchio and Eva Nogales transport along microtubules (such as axonal transport) or for cell motility (such as Abstract | Next year will be the 50th anniversary of the discovery of tubulin. ciliary or flagellar motion). The interaction To celebrate this discovery, six leaders in the field of microtubule research reflect of kinesin with microtubules was a model on key findings and technological breakthroughs over the past five decades, system, because it was clear that only a discuss implications for therapeutic applications and provide their thoughts on relatively small number of kinesins must what questions need to be addressed in the near future. be capable of moving small vesicles along microtubules. A related question was how microtubule growth and shrinkage could Identifying the main component of Rebecca Heald. In the mid-1990s, one generate force to move chromosomes microtubules was obviously the pressing question was why microtubules during mitosis. Polymerization and pressing task in the field around 50 years ago. in cells were so much more dynamic than depolymerization forces were very What key questions were being pursued microtubules assembled from purified mysterious: how could you hold on to the when you entered the arena of tubulin. Neuronal microtubule-associated end of a depolymerizing microtubule? How microtubule research? proteins (MAPs) had been identified could a microtubule grow, and new tubulin and studied (in large part because they subunits get in, if its end was pushing up Gary Borisy. Actually, I had no idea in the co-purified with tubulin isolated from brain against something? What role did the GTP cap early 1960s that I was entering the arena tissue, where it is most abundant), but these have, and how was energy from GTP used to of microtubule research, because it hadn’t proteins all stabilized microtubules, and generate pulling or pushing forces? How did yet been defined as an arena. Although factors that induced the transition from MAPs regulate growth and shrinkage? the term ‘microtubule’ was first coined in growth to shrinkage (catastrophe) were 1963, the structures had not, in fact, been unknown. A related question was how the Carsten Janke. I entered the field of observed in most cells, because the fixation microtubule cytoskeleton transformed microtubule research somewhat through methods used at the time did not preserve from a relatively stable interphase array to a a back door. During my Ph.D. studies, them. It was only after the introduction of highly dynamic bipolar spindle in mitosis. I worked on the role of the MAP tau in glutaraldehyde as a fixative, also in 1963, At the time, the centrosome was thought neurodegeneration, and in my postdoctoral that they began to be observed routinely. to be the sole ‘microtubule-organizing’ work, I characterized new kinetochore The concept of the microtubule as a centre of the cell, determining the site of protein complexes in budding yeast. This ‘ubiquitous’ cytoskeletal structure wasn’t microtubule growth and their polarized was in the late 1990s, and at the time, the put forward until 1965. My entry point orientation. In my opinion, the discovery field had already expanded a lot: different into the field was mitosis: I wanted to get of a large family of kinesin motor proteins, research communities pursued their own a molecular handle on how cells divide. as well as cytoplasmic dynein, spawned interests. There were many parallel advances Working with Ed Taylor at the University key investigations into how cellular factors at the time, such as the biochemical and of Chicago (Illinois, USA), we were trying affect microtubule behaviour. The diverse functional dissection of the kinetochore, to identify and purify the molecule that activities of different motor proteins to the understanding of the role of primary bound to colchicine, because colchicine was induce catastrophe, crosslink and move cilia as the ‘cell antennae’, and advances in known to specifically inhibit mitosis. We microtubules relative to one another the characterization of neuronal transport had no preconceived idea about what the revealed the ability of microtubule arrays mediated by microtubules. Specifically colchicine target would be, but we believed to ‘self-organize’. This process allows regarding microtubule research, I think that identifying the target would teach us the spindle to form in the absence of a highlight of the 1990s and 2000s was something important about mitosis. So, centrosomes — for example, during female the use of highly sophisticated, in vitro the key questions for us at the time were meiosis in many animal species, or when reconstructions of microtubule assemblies how to isolate, purify and characterize the the centrosome is inactivated genetically from recombinant components, and their colchicine-binding protein and then to or by laser ablation. An important ongoing biophysical characterization. This allowed establish its identity1,2. challenge is to fully understand how the definition of minimal functional units 322 | MAY 2016 | VOLUME 17 www.nature.com/nrm ©2016 Mac millan Publishers Li mited. All ri ghts reserved. ©2016 Mac millan Publishers Li mited. All ri ghts reserved. PERSPECTIVES of microtubule assemblies such as the agents that targeted tubulin and affected to be used on cytoskeletal filaments. This microtubule arrays of the mitotic spindle. dynamic instability were being discovered. was the time when Dick Wade (CNRS) was A second highlight was the amazing advances But what I remember as the most exciting imaging microtubules and proposed the in imaging of microtubule structures development at the time was the publication lattice accommodation theory to explain the in vivo, which were driven by substantial of the structure of actin by Ken Holmes existence of microtubules with different improvements in light microscopy. and colleagues (Max Planck Institute at protofilament numbers. Also using Heidelberg, Germany). It became obvious cryo-EM, the Mandelkows and Ron Milligan Andrea Musacchio. When I entered the that there was also a pressing need for a (Scripps Research Institute, California, field, approximately 15 years ago, studies on structure of tubulin. Many were trying to USA) visualized the depolymerization of my main research interest, the kinetochore, crystallize it, like actin, in an inhibited form. microtubules by protofilament peeling, had remained traditionally distinct from At the same time, the new technique of producing images that inspired me and studies of microtubules as cytoskeletal cryoelectron microscopy (cryo-EM) started influenced my scientific career. components. The search-and-capture model offered a conceptual basis for how microtubules that interact with kinetochores The contributors* might become selectively stabilized to Gary Borisy completed his Ph.D. in 1966 at the University of Chicago, Illinois, USA, and was formerly generate kinetochore fibres, but the a member of faculty at the University of Wisconsin and Northwestern University, USA, and President/ mechanism was obscure. The critical gap in Director of the Marine Biological Laboratory, Massachusetts, USA. He is best known for his work on knowledge was in our understanding of how the molecular biology of the cytoskeleton. Currently, he is a Senior Investigator at the Forsyth kinetochores, which are among the largest Institute in Cambridge, Massachusetts, and is exploring the biogeography of microbial communities (if not the largest) microtubule-binding at the micrometre scale through combinatorial labelling, spectral imaging and metagenomics. machines, bind to and stabilize microtubules Gary Borisy’s homepage: http://forsyth.org/person/scientist/gary-borisy to link them to chromosomes. Research Rebecca Heald is a Professor in the Department of Molecular and Cell Biology at the University of therefore focused on the identification of California Berkeley, USA. She pursued her Ph.D. training with Frank McKeon at Harvard University, potential linking proteins and how they are Cambridge, Massachusetts, USA, and carried out postdoctoral work with Eric Karsenti at the harnessed to align the sister chromatids European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. Her laboratory is to the metaphase plate, and later to part interested in mechanisms of spindle assembly, cell division and size control. them to the opposite spindle poles. The Jonathon Howard has a Ph.D. from the Australian National University in Canberra, Australia, and identification of an array of new kinetochore was Professor of Physiology and Biophysics at the University of Washington in Seattle, USA, before proteins in the early 2000s facilitated the joining the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, as a identification of such proteins. Most notably, group leader and director. The Howard laboratory recently moved to Yale University, New Haven, teams led by Arshad Desai (University of Connecticut, USA. His research interests include molecular motors and cytoskeletal polymers, especially their roles in
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