Causes et conséquences de l’aneuploïdie / Causes and consequences of aneuploidy

Séminaire organisé Marie-Hélène Verlhac (CIRB, Collège de France, Paris) et Renata Basto (Institut Curie, Paris) par du 6 au 11 juin 2016

Participants

Angelika Amon, Renata Basto, Buzz Baum, Don W. Cleveland, Arshad Desai, Arnaud Echard, Daniele Fachinetti, Fanni Gergely, Ulrike Gruneberg, Andrew Holland, Keith Jones, Simon Lane, Thierry Lorca, Ana Losada, Raquel Oliveira, Jan-Michael Peters, Simonetta Piatti, Jonathon Pines, Zuzana Storchova, Marie-Emilie Terret, Marie-Hélène Verlhac

Résumé

Les systèmes de point de contrôle du cycle cellulaire ont évolué afin de permettre une ségrégation fidèle des chromosomes entre cellules filles. Lorsque ces points de contrôle sont défaillants, des erreurs numériques dans la répartition des chromosomes entre les deux cellules filles, appelées aneuploïdies, peuvent apparaître. Ces aneuploïdies sont associées à de nombreuses maladies, comme le cancer et peuvent conduire à des malformations développementales. Lors de ce congrès aux Treilles nous avons énormément discuté de l’origine des aneuploïdies : défauts dans la machinerie de ségrégation des chromosomes (le fuseau de division), dans la machinerie de contrôle de l’alignement des chromosomes (les kinétochores et les points de contrôle du fuseau), défauts dans les complexes impliqués dans le maintien de la cohésion entre chromatides sœurs, importance du contrôle des activités enzymatiques, tel le jeu de kinases et de phosphatases ainsi que les enzymes (APC/C) responsables de la dégradation de substrats clés du cycle cellulaire. Nous avons aussi discuté des conséquences de ces aneuploïdies : tel le cancer induit chez la souris par la présence de centrosomes surnuméraires, les conséquences de la polyploïdie sur le développement du cerveau de la larve de drosophile, ou de la triploïdie sur la croissance cellulaire. Nous estimons que l’objectif premier du congrès, faire émerger une discipline et promouvoir les interactions/collaborations entre chercheurs, a été atteint. Ceci, non seulement grâce au cadre exceptionnel qu’offre la fondation des Treilles mais aussi grâce à la gentillesse de l’ensemble des personnels sur place, leur disponibilité et enfin grâce à ces longs moments de discussion qui permettent de vrais échanges scientifiques. Pour tout cela, les participants souhaitent remercier chaleureusement la Fondation des Treilles et en particulier feue Anne Gruner Schlumberger, qui était de toute évidence un mécène éclairé et une visionnaire.

Compte-rendu (en anglais)

The meeting “Causes and Consequences of aneuploidy” gathered 21 scientists from many different countries worldwide, at the Fondation des Treilles.

This meeting went well beyond our initial expectations. An exceptional friendly setting was very rapidly established, which contributed for brilliant and informal scientific discussions, setting the ground for future collaborations.

This meeting brought together 6 junior scientists (<10 years after PhD award) and 12 senior scientists (>10 years after PhD award). Additionally, young independent group leaders, which have established their labs less than 10 years ago, were present in equal proportion to senior group leaders. Importantly, gender balance was also respected with 10 female and 11 male speakers.

The aim of this meeting was to gather scientists working on aneuploidy. Most cells from our body contain a diploid genome content, where every gene is present in two copies. Throughout development and adult life, it is essential to maintain genome stability to avoid the generation of cells with unequal chromosome numbers, aneuploid cells, which can lead to several pathological conditions such as growth disorders or cancer. The scientists present at this meeting work on several aspects related with aneuploidy that span from the processes that regulate cell division, both meiosis and mitosis, to the consequences of becoming aneuploid.

On the first day, Thierry Lorca (CRBM, Montpellier, France) told us about the role of Greatwall kinase in regulating mitotic entry and in promoting transformation of mammary gland cells. Ulrike Gruneberg (Oxford University, Oxford, UK) described the fascinating role of phosphatases and how these proteins regulate microtubule spindle assembly and the activation and inhibition of the mitotic checkpoint. Jan-Michael Peters (IMP, Vienna, Austria) depicted the unconventional function of Cohesins in gene expression regulation. Of outstanding interest was the combination of TIRF microscopy to ascertain Cohesin loading and movement on naked DNA fibers. Ana Losada (CNIO, Madrid, Spain) and Raquel Oliveira (IGC, Oeiras, Portugal) described work related to the role of cohesin in genome organization and in sustaining chronic errors in chromosome segregation.

On the second day, Renata Basto (I. Curie, Paris, France) started the session by describing the tissue-specific consequences of polyploidy during development and how whole genome duplications can lead to tumour formation. Andrew Holland (J. Hopkins, Baltimore, USA) told us about the consequences of centrosome amplification and tumour formation in mouse models. Further, he described novel findings related with the activation of p53 in response to centrosome loss. Fanni Gergely, (CRUCK CI, Cambridge, UK) presented her work related with how growth failure syndromes are induced in response to centrosome loss in mice. Of particular interest, the susceptibility of the mammalian brain to mutations in centrosome genes was discussed. Later, Buzz Baum (LMCB-MRC, London, UK) told us about the consequences of cell confinement on spindle morphogenesis and cell division. Marie-Emilie Terret (CIRB, Paris, France) showed us the role of the actin cytoskeleton in generating cortical tension and how this process influences spindle positioning and chromosome alignment in mouse oocytes during meiosis. Arnaud Echard (I. Pasteur, Paris, France) described a novel role for the Rab35 GTPase in lumen opening, which couples cytokinesis with apico-basal polarity establishment and with cyst formation.

The third day begun with Don Cleveland (Ludwig Institute for Cancer Research, UCSD, San Diego, USA) relating the underlying mechanisms involved in centromere specification and functioning. Simonetta Piatti (CRBM, Montpellier, France) told us about the identification of the mechanisms involved in mitotic slippage in particular the role of the SAGA complex in this response. Jonathon Pines (Gurdon Institute, Cambridge, UK) showed us how the Spindle Assembly Checkpoint inhibitory response is generated to efficiently inhibit APC/C activation through sequestering of its activators. Daniele Fachinetti (I. Curie, Paris, France) described his latest findings on the assembly of a functional centromeric unit, in particular how CENP-A, CENP-B and CENP-C coordinate this process. Marie-Helene Verlhac (CIRB, Paris, France) told us how defects in early spindle morphogenesis or PCM assembly can impact meiosis I and lead to the generation of aneuploid oocytes. Arshad Desai (Ludwig Institute for Cancer Research, UCSD, San Diego, USA) showed us the enormous potential of the C. elegans embryo to molecularly dissect the pathways that control chromosome attachments and oscillations prior to anaphase onset. Angelika Amon (MIT, Boston, USA) related findings concerning spindle assembly in 2D and 3D-culture and how polarity and cell adhesion influence cell division and chromosome segregation. Additionally, she told us about her latest findings on the elimination of aneuploid cells. Extremely interesting discussions were generated on the role of p53 in detecting whole chromosome aneuploidies.

On the last day, Zuzana Storchova (MPI, Martinsried, Germany) described the mechanisms by which aneuploid cells accumulate DNA damage leading to chromosome instability and how this can impact tumorigenesis. Keith Jones (Southampton University, Southampton, UK) told us about the mechanisms that contribute to Spindle Assembly Checkpoint silencing during meiosis I in mouse oocytes. Simon Lane (Southampton University, Southampton, UK) described an original method to reduce oocyte volume to ascertain scaling of APC/C activation and checkpoint inhibition.

With much regret, this meeting came to an end! Many factors contribute to its success. Among them, the friendly atmosphere, the excellence of science combined with the peaceful and beautiful surroundings, the sunny coffee breaks and the tasty food, made this a unique opportunity to foreseen future directions in the aneuploidy field. We can only truly thank the Fondation des Treilles for providing us with this outstanding opportunity.