Causes and consequences of aneuploidy

Participants :

Angelika Amon, Renata Basto (Organiser), 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 (Organiser).

Verlhac_Basto_Aneuploidie_Groupe2016

 

Causes and consequences of aneuploidy
by Marie-Hélène Verlhac and Renata Basto
6 – 11 June, 2016 

Résumé

Cell Cycle checkpoints have evolved ensuring correct segregation of chromosomes between daughter cells. When these checkpoints become defective or weakened, numerical aberrations of whole chromosomes, called aneuploidy, present in daughter cells can arise. These aneuploidies are often associated with many diseases, such as cancer and can also lead to developmental disorders. During our Treilles meeting, we have intensely discussed the origin of aneuploidies: defects in spindle assembly, defects in kinetochore assembly and kinetochore-associated checkpoints, defects in Cohesin complexes required to hold chromatids together, importance of controlling key kinases and phosphatases activities as well as enzymes such as (APC/C) which ensure precise temporal degradation of key cell cycle targets. We have also discussed the consequences of aneuploidies: such as cancer induced in the mouse by extra-centrosomes, consequences of polyploidy on larval brain developmental of drosophila, or on triploidy on cell growth. The main goal of this meeting, allow the emergence of a new discipline and promote interactions/collaborations between biologist experts, was reached. Thanks, not only to the exceptional environment offered by the Treilles foundation, thanks also to the extreme care and availability of all personnel on site but also thanks to these long moment of scientific discussion rendered possible by the format of the meeting. For all this, participants of the meeting would like to deeply thank the Treilles foundation, and in particular late Anne Gruner Schlumberger, who certainly was a visionary.

Key words: Aneuploidy- cell cycle regulation- cell division

Review

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.

Angelika Amon Renata Basto Buzz Baum Don 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 Causes and consequences of aneuploidy - Causes et conséquences de l'aneuploïdie - Fondation des Treilles
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