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Report Individual Group Leaders Report individual group leaders Site visit Hubrecht Institute 10-11 November 2014 - 2 - INDEX Group leader Group name Page Jeroen Bakkers Cardiac Development and Genetics ................................................ 05 Hans Clevers Lgr5 stem cells, Wnt signaling & cancer .......................................... 11 Menno Creyghton Neuro epigenetics ............................................................................ 19 Edwin Cuppen Genome Biology and Medical Genetics ........................................... 25 Eelco de Koning Diabetes and islet neogenesis ......................................................... 33 Wouter de Laat Biomedical Genomics ...................................................................... 39 Jeroen den Hertog Protein-tyrosine phosphatases in development ............................... 47 Jacqueline Deschamps Genetics of morphogenesis during axial elongation in the mouse embryo ............................................................................................. 53 Niels Geijsen Stem Cell Modeling of human genetic disease ................................ 61 Daniele Guardavaccaro Ubiquitin ligases and cancer ............................................................ 67 Jop Kind Spatiotemporal regulation of genomic function ................................ 73 Puck Knipscheer Molecular mechanisms and regulation of DNA repair...................... 77 Rik Korswagen Wnt signaling in development and disease ...................................... 83 Catherine Rabouille Secretion regulation ......................................................................... 89 Catherine Robin Hematopoiesis and stem cells during embryonic development ....... 95 Alexander van Oudenaarden Quantitative biology of development & stem cells ......................... 103 Jacco van Rheenen Cancer Biophysics ......................................................................... 113 Eva van Rooij Molecular Cardiology ..................................................................... 121 - 3 - - 4 - Jeroen Bakkers Key publications (2008-2014) Junker JP, Noël ES, Guryev V, Peterson KA, Shah G, Huisken J, McMahon AP, Berezikov E, Bakkers J* and van Oudenaarden A*. Genome-wide RNA tomography in the zebrafish embryo. *shared corresponding authors. Cell in press. Chetaille P, Côté J, Burkhard S, Houde C, Preuss C, Piché J, Gosset N, Leclerc S, Wünnemann F, Cameron M, Castilloux J, Thibeault M, Gagnon C, Galli A, Tuck A, Hickson G, Amine N, Boufaied I, Lemyre E, Santa Barbara P, Faure S, Jonzon A, Dietz H, Gallo-McFarlane E, Benson W, Zhan SH, Shen Y, Jomphe M, Jones SJM, Bakkers J and Andelfinger G. A human dysrhythmia syndrome affecting heart and gut is associated with mutations in SGOL1. Nat. Genet. in press. Noël ES, Verhoeven M, Lagendijk AK, Tessadori F, Smith K, Choorapoikayil S, den Hertog J, Bakkers J. (2013) A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality. Nat. Commun. 4:2754. Mugoni V, Postel R, Catanzaro V, De Luca E, Digilio G, Turco E, Silengo L, Murphy MP, Medana C, Stainier DYR, Bakkers J and Santoro MM. (2013) Ubiad1 Is an Antioxidant Enzyme that Regulates eNOS Activity by CoQ10 Synthesis. Cell 152(3):504-518. Smith K, Chocron S, von der Hardt S, de Pater E, Soufan AT, Bussmann J, Schulte Merker S, Hammerschmidt M and Bakkers J. (2008). Rotation and asymmetric development of the zebrafish heart requires directed migration of cardiac progenitor cells. Dev. Cell 14; 287–297. - 5 - Dr. ir. Jeroen Bakkers Cardiac Development and Genetics Group members Postdocs: Emily Noël, Federico Tessadori, Ina Strate Graduate students: Lotte Koopman, Silja Burkhard, Fabian Kruse, Melanie Laarman Technicians: Sonja Chocron Curriculum vitae group leader Name: Dr. ir. Jeroen Bakkers Date of birth: 13-05-1970 Nationality: Dutch Education/positions 1988-1994 MSc, Wageningen University 1994-2000 PhD, Leiden University 2000-2003 Postdoc, Max-Planck Institute, Freiburg, Germany 2003-2008 Hubrecht Institute, Junior group leader 2008-now Hubrecht Institute, Senior group leader Memberships - Member editorial board Journal of Cardiovascular Development and Disease - President of the Dutch Society of Developmental Biology (DSDB). Awards - 2000 PhD degree with highest distinction (Cum Laude), Leiden University - 2009 NWO/Vidi career grant Other activities • Organizer meetings: 2008, 2011, 2013 National meeting on Cardiac Development, Utrecht. 2008 KNAW colloquium “Cardiac Development, Disease and Stem Cells”, Amsterdam. 2011 1st meeting of the Dutch Society for Developmental Biology (DSDB), Utrecht. Thesis advisor for (graduation date) • Ruben Postel, (May 2008) • Manon Verhoeven, (April 2009) • Emma de Pater, (June 2010) • Anne K. Lagendijk, (December 2011) Invited speaker on meetings (2008-2014) 2008: Weinstein meeting for Cardiovascular Development, Houston, USA 2009: American Heart Association (AHA) Scientific Sessions, Orlando, USA; European Heart Failure meeting (ECS), Nice, France; Joint Meeting 2009 Anatomische Gesellschaft – Nederlandse Anatomen Vereniging, Antwerpen, Belgium; Dutch-German meeting on Cardiovascular research, Hamburg, Germany; Zebrafish PI meeting, Asilomar, USA 2010: EUGeneHeart Symposium, Brussels, Belgium; Basic Cardiovascular Science Meeting of the European Society of Cardiology, Berlin, Germany; Heart Failure Congress (ESC), Berlin, Germany 2011: International Weinstein meeting for Cardiovascular Development, Cincinnati, USA; Zebrafish PI meeting, Asilomar, USA 2012: International Weinstein meeting for Cardiovascular Development, Chicago, USA; Basic Cardiovascular Science Meeting of the European Society of Cardiology, London, UK; ESC Working Group Cardiac Development Meeting, Amsterdam, NL; International meeting on BMP signaling in Development and Disease, Lake Tahoe, USA - 6 - 2013: Zebrafish PI meeting, Asilomar, USA; Zebrafish Development and Disease meeting, Bristol, UK 2014: Zebrafish Disease Models Conference, Madison, USA; Graduate School Student Meeting Münster, Germany; CDBC Spring symposium, Charleston, USA Grants (2008-2014) • 2014 NWO middelgroot (equipment), co-PI € 550,000 • 2013 Nederlandse Hartstichting, co-PI € 250,000 • 2013 ZonMW TOP grant, PI € 290,000 • 2013 CVON CardioVasculair Onderzoek Nederland, co-PI € 200,000 • 2012 CVON CardioVasculair Onderzoek Nederland, co-PI € 450,000 • 2012 NWO PhD fellowship, to S. Burkhard € 200,000 • 2011 NWO ZonMW middelgroot, co-PI € 400,000 • 2009 EU FP7 BIOSCENT, co-PI € 250,000 • 2009 NWO Vernieuwingsimpuls (VIDI), career grant), PI € 600,000 Total: € 3,200,000 Previous research My research is centred on understanding mechanisms of cardiac development and disease using the zebrafish as a model system. During my postdoctoral training I had worked on the role of bone morphogentic protein (BMP), a TGF-ß related growth factor, during gastrulation. I had worked with several zebrafish mutants deficient in BMP signalling components and that displayed cardiac phenotypes that had not been described previously. Considering the advantages of the zebrafish model (good genetic tools, rapid development and transparency of the embryo, and early development independent of functional cardiovascular system), and the early lethality of mouse mutants defective in BMP signalling made me decide to study the role of BMP signalling in cardiac development when starting my own research group at the Hubrecht Institute. This initial work let to the discovery that BMP signalling is required at post-gastrula stages to regulate the asymmetric development of the heart (Chocron et al. (2007) Dev. Biol.). During heart tube formation the inflow pole of the linear heart tube will be positioned left from the embryonic midline after which it forms an S-shaped heart tube with the ventricle moving towards the embryonic right side. Our work demonstrated that BMP signalling is required at two different stages to regulate the asymmetric development of the heart tube; 1) BMP signalling is required to establish correct expression of early laterality markers (such as left-sided Nodal expression) during early somite stages. 2) During late somite stages when asymmetric Nodal expression is established BMP signalling is required for the leftward positioning of the heart tube. To reveal the cell migration behaviour of cardiac progenitor cells during asymmetric heart tube formation I combined confocal time-lapse microscopy with cell tracking tools. Doing so we discovered an asymmetric cell behaviour that results in the clock-wise rotation of the cardiac field during heart tube formation. In addition we found that BMP growth factors can influence cell migration behaviour and regulate the direction of heart tube assembly (Smith et al (2008) Dev. Cell). Other labs have independently confirmed this rotation behaviour and demonstrated that also Nodal growth factors influence migration behaviour of cardiac progenitor cells suggesting a close relation of BMP and Nodal signalling during this process. To allow an unbiased approach to identify components that regulate the left-right axis and/or asymmetric organ development my lab performed several ENU-based forward genetic screens that used alterations in heart laterality (leftward position and directional heart looping) as a read-out (excluding mutants with overt cilia related defects). We screened around 1200 F2 families (about 100.000 embryos) over a period of 2-3 years resulting in the validation of 10 independent mutant lines. Interestingly we found that these mutant lines fall into two different
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