Mechanisms and regulatory circuits mediating chromosome segregation in meiosis and mitosis / Les mécanismes et les circuits de régulation permettant la ségrégation des chromosomes

Séminaire organisé par Katja Wassmann (IBPS – UPMC, Paris, France) et Thomas U. Mayer (University of Konstanz, Germany) du 6 au 11 octobre 2014

Participants

Anna Castro, Silke Hauf, Timothy Hunt, Daisuke Izawa, Jean-Paul Javerzat, Geert Kops, Christian Lehner, Thierry Lorca, Marcos Malumbres, Adele Marston, Thomas U. Mayer, Bela Novak, Terry Orr-Weaver, Olaf Stemmann, Kikuë Tachibana-Konwalski, Tomoyuki Tanaka, Katja Wassmann, John Weir, Wolfgang Zachariae

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Summary

The segregation of chromosomes is one of the most fundamental processes in biology. Despite the fact that mitosis and meiosis fascinate scientists since its first description more than 100 years ago, the underlying mechanisms and regulatory circuits are still poorly understood. Therefore, we decided to bring together experts which all share a vital interest in cell cycle research, yet have distinct complementary scientific expertise. This seminar gathered cell cycle specialists working on various model systems ranging from yeast and drosophila to Xenous oocytes and mouse models, structural biologists, and specialists in mathematical modeling. A third of the participants were young researchers who are going to or have recently set up their independent research group. The unique setup of the Fondation des Treilles meetings provided an ideal platform for mutually illuminating discussions where key questions in future cell cycle research were defined and multidisciplinary strategies to address these open questions were revealed. We are convinced that this meeting served as a nucleation center for future interdisciplinary research efforts in the field of cell cycle research.

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Compte-rendu (en anglais)

Participants were selected for their common interest in understanding mitotic and meiotic chromosome segregation. Usually we had three presentations in the morning, and four presentations in the afternoon. The seminar was started with a keynote lecture by the Nobel Prize laureate Tim Hunt. He gave an introduction on the key questions that have been studied in the field and the recent shift in interest from the regulation of kinases (which phosphorylate their substrates) to phosphatase, which counteract the very same kinases. He presented also the most recent work from his laboratory on the identification of Ensa, an inhibitor of the phosphatase PP2A-B55. Thomas U. Mayer gave the following talk on entry into the first meiotic division in Xenopus laevis oocytes. He presented recent, unpublished work showing that the E3 ubiquitin ligase APC/C is not required for maintaining oocytes arrested before entry into meiosis I, but on the contrary, for entry into meiotic M-phase. It is attractive to speculate that the mechanisms for meiotic entry he discovered in X. laevis oocytes apply also to mammalian oocytes. His presentation was followed by the talk of Anna Castro. Her group has discovered Arpp19, a close homologue of Ensa, as being required for counteracting PP2A-B55 for proper cell cycle progression. Arpp19 and Ensa are both phosphorylated and thereby activated by a kinase named Greatwall (Gwl). In her talk she showed that Gwl overexpression promotes cell transformation and increases tumor growth in mice, and in her talk she presented data on the question of whether this was dependent on Arpp19 and Ensa. In the afternoon, Marcos Malumbres then talked about how mammalian cells can die in mitosis which is an important issue to understand how tumor cells respond to drugs targeting mitotic kinases. Christian Lehner‘s talk on drosophila male meiosis brought important insights into the mechanisms of chromosome segregation in a chiasmata-independent manner. Using the budding yeast S. cerevisiae as a model system, Adèle Marston asked how kinetochores in meiosis I are attached to the bipolar spindle and whether they are stronger than in mitosis. John R. Weir, currently a postdoc in the lab of A. Musacchio, presented his data on the very ambitious goal of reconstituting and characterizing a human kinetochore, a multiprotein complex connecting chromosomes to the mitotic spindle.

The next morning was started by a talk from Olaf Stemmann on the role of the peptidyl-prolyl-isomerase Pin1 for regulating Securin-dependent inhibition of Separase, during mammalian mitosis. Using the fission yeast S. pombe as a model system, Jean-Paul Javerzat presented his recent results on the regulatory circuits for DNA release from Cohesin. Kikuë Tachibana Konwalski addressed whether reloading of Cohesin occurs during the extended prophase I arrest before entry into the meiotic divisions, in mouse oocytes by using genetically modified mice. In the afternoon, Katja Wassmann showed that the spindle assembly checkpoint protein BubR1 is absolutely essential for correct chromosome segregation in mouse oocyte meiosis. Tomoyuki U. Tanaka talked about the role of the kinase Aurora B in correcting faulty microtubule kinetochore attachments in the context of kinetochore attachments to the microtubule lateral side, and to the microtubule end. He also discussed the transition from a low- to a high- mechanical tension state of kinetochores. Daisuke Izawa, a postdoc from the lab of J. Pines, showed data on the in vitro reconstitution of the mitotic checkpoint complex, which is required for metaphase arrest upon spindle checkpoint activation. The last talk of the day by Geert J.P.L. Kops also dealt with spindle assembly checkpoint control. He discussed the inactivation of the checkpoint once all kinetochores are correctly attached through opposing phosphatases.

The following third day of the seminar we had presentations only in the morning to leave time in the afternoon for visiting the surroundings of the Domaine de Treilles in small groups. The session was started by Wolfgang Zachariae, who presented recent data on progression through the meiotic divisions, and how meiosis is linked to the differentiation program for spore formation, in budding yeast. Thierry Lorca talked about the kinase Greatwall and its role in the establishment of CSF arrest in Xenopus oocytes. Again, the role of Arpp19 for inhibition of PP2A was discussed, but this time in the context of maintaining oocytes arrested in metaphase of meiosis II for fertilization to occur. Terry Orr-Weaver discussed translational changes and regulated proteolysis that take place at the oocyte to embryo transition, in drosophila.

On the last day of our seminar we started with a presentation from Bela Novak. He gave a talk on the mathematical modeling of the regulation of the G2/M transition through nutritional modulation and relative to cell size. The final talk by Silke Hauf was focused on the balance of Cyclin B and Securin degradation relative to each other as fission yeast cells exit mitosis, to understand how the order of events is implemented in anaphase. The seminar was concluded by a final discussion, animated by Tim Hunt. All participants agreed that the seminar was extremely useful because of the relaxed setting and the small number of participants, allowing for in-depth discussions. The mix of young researchers at the postdoctoral stage, young group leaders, and experienced, senior researchers, combined with the interdisciplinarity of the seminar is expected to be very helpful for future projects of the participants. All participants agreed that a similar seminar should be organized in a couple of years, to further foster interactions and common projects in the long term.