MGC-Bulletin, Nr. 51, September 2014 In dit nummer:

MEDISCH-GENETISCH CENTRUM ZUID-WEST NEDERLAND - MGC

MGC-Bulletin, Nr. 51, September 2014 In dit nummer: Onderwijs voor promovendi .......................... 2 Coördinatie en redactie: M. Nivard/I. Braxhoven

PhD Teaching Programme Committee ......... 3

e-mail: [email protected]

MGC Promovendi Workshop 2015 ................ 3

: 071-5269605/69601

Promoties ....................................................... 3 Nieuwe medewerkers ..................................... 4 Lezingen/symposia ........................................ 6

Sectie 'DNA herstel-mechanismen' ............... 7 Sectie ‘Lysosomal Storage Diseases’ .......... 7 Verkregen subsidies ...................................... 7 Personalia/Prijzen .......................................... 8 Overige mededelingen ................................... 8 MGC-Bulletin no. 52 ....................................... 9 Program 24th MGC Symposium .................... 10

Abstracts 24th MGC Symposium .................. 11 De MGC bestuurders en hun instituten ....... 19 Andere instituten/groepen binnen het MGC 19 Het MGC secretariaat .................................... 19

De uitreiking van de Prinses Beatrix Spierfonds wetenschapsprijs aan Silvère van der Maarel. Foto: Frank van Beek

Het Centrum is een initiatief van het Universitair Medisch Centrum Rotterdam en het Leids Universitair Medisch Centrum

Onderwijs voor promovendi Het aanbod van cursussen voor promovendi in het LUMC is tegenwoordig online beschikbaar. Deze informatie is te vinden op http://albinusnet.lumc.nl/home/.

A course "From Molecular Pathogenesis to Targeted Therapy " will be organized from 27 – 31 October 2014 in Leiden. The aim of this course is to give an overview of intracellular signalling processes that are activated by hormones, cytokines and growth factors, as well as state-of-the-art technology used to study signal transduction in vivo and in vitro. Teaching will occur by state-of-the-art lectures and interactive tutorial. For more info see www.medgencentre.nl.

A course "Live cell and super resolution imaging" will be organized from 27-31 October 2014 in Rotterdam. The aim of the course is to provide a comprehensive introduction to the field of translational cancer research. This five day course consists of lecture sessions in the morning and practical sessions in the afternoon; on some days also evening sessions with a dinner. In the final session on Friday afternoon participants will present and discuss the results of their practical work. For more info see www.medgencentre.nl

A course on "Safely working in the lab” will be given in December in Leiden. The following points will be addressed: safe microbiological techniques; radionuclides; carcinogenic agents; blood, viruses; radiation. The course is also open for other new personal of the MGC. The course will be given twice a year depending on the interest in collaboration with the Department VSM of the LUMC. Apply through the MGC web site: www.medgencentre.nl or for people from the LUMC via ‘bedrijfsopleidingen’. From our sister school Molecular Medicine the following courses are available:  Photoshop and Illustrator CS6 workshop: September-October, a hands-on full day workshop on the

MGC-Bulletin no. 51; September 2014

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programs Photoshop and Illustrator CS6. These programs are used for image enhancement and drawing high quality graphs, tables and other figures  Indesign CS6 Workshop: September – October, a half-day Workshop on Adobe Indesign CS6.  Biomedical Research Techniques: 13 – 17 October. A basic five-day course on several lab techniques. The program covers: Day 1: primers and probes, sequencing, SNP analysis, methylation; Day 2: RNA, RNA expression arrays, RT PCR, siRNA, data mining; Day 3: site visit DNA/RNA labs; proteomes, mass spectrometry; Day 4: ELISA, cytotoxicity, flow cytometry, phage antibody display; microscopy; Day 5: Applied molecular imaging: MRI, CR, nuclear, optical in vivo and site visit proteomic labs.  Translational Imaging Workshop by AMIE: from mouse to man: 11-14 November. The aim of this 4-day workshop is to give a broad introduction into preclinical and translational molecular imaging techniques and their applications in biology and medicine.  SNP Course: 17-21 November. An annual 5-day course on SNP and complex diseases, including hands-on computer practicals. Basic knowledge of the central molecular biological is required. For detailed information & registration info www.molmed.nl

Courses organized by Boerhaave CME:  Advanced Genetic & Genomic Data analysis: 20 – 22 October. This course in genetic association analysis includes now highly relevant topics such as the analysis for multidisciplinary research with novel omics datasets. It covers analysis and practical issues of rare variants detected by next generation sequencing and gene expression analysis. Participants need to bring their own laptop.  Survival Analysis: 3-7 November. Survival analysis is the study of the distribution of life times, i.e. the times from an initiating event (birth, diagnosis, start of treatment) to some terminal event (relapse, death). During the

course different types of censored data will be introduced and techniques for estimating the survival function by employing both parametric and nonparametric methods will be illustrated. Multiplicative hazards regression models, testing and inference techniques will be studied in great details. Special aspects as timedependent covariates effects, stratification, time and prediction will be introduced. Techniques to be used to assess the validity of the hazard regression model will be discussed.  Meta Analysis: 5-7 November. Metaanalyse is een kwantitatieve samenvatting van een aantal studies binnen een systematisch literatuuronderzoek. Met deze driedaagse cursus krijgt u een overzicht van de principes van systematisch literatuuronderzoek en de statistische methoden die voor meta-analyse worden gebruikt. De statistische analyses worden geoefend met het programma STATA. Na deze cursus kunt u artikelen over literatuuronderzoek doorgronden en op kwaliteit beoordelen en kunt u zelf een (eenvoudige) metaanalyse uitvoeren. For detailed information & registration: www.boerhaavenet.nl.

PhD Teaching Committee

The MGC-PhD student workshop is a 4day event organized every year by PhD students for PhD students. During this workshop PhD students get the chance to:  - exchange knowledge in an informal and relaxed way, through posters and presentations  - build their own network during social events and free time The workshop is meant for PhD students who are doing their research in one of the MGC departments. The attendance to the workshop is part of the PhD program and PhD students should attend at least three times during their PhD.

Foto: Martí Quevedo

De prijswinnaressen tijdens de workshop: Valliveti Subramanyam Reddy (beste poster) en Risha Smeding (beste lezing)

Programme

Since 2011 the MGC has a newly formed PhD Teaching Programme Committee. Members of the committee are: Raymond Poot and Kerstin Wendt of the Erasmus MC and Dorien Peters, Harry Vrieling and Madeleine Nivard of the LUMC. The committee will focus primarily on evaluation of the existing course program and will advise on new courses or teaching activities (Contact email address: [email protected]).

MGC Promovendi Workshop 2015 The 21st MGC-PhD workshop was held in Münster, Germany and was a big success. The 22nd workshop will be held in June 2015. Venue is not known yet. For more information see www.mgcworkshop.nl.


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Promoties Anika Vaarhorst is op 13 mei in Leiden gepromoveerd op het proefschrift "Genetic and metabolomic approaches for coronary heart disease risk rediction". Promotor: Prof. P. Slagboom; co-promotor: Dr. B. Heijmans. Ingrid Verhaart is op 20 mei in Leiden gepromoveerd op het proefschrift "Optimising antisense oligonucleotidemediated exon skipping for Duchenne muscular dystrophy". Promotor: Prof. G. van Ommen; co-promotor: Dr. A. AartsmaRus. Arjan Theil is op 4 juni gepromoveerd in Rotterdam op het proefschrift "Functional analysis of TTDA: from human to mouse – big impact of a small protein". Promotor:

Prof. J. Hoeijmakers; co-promotor: Dr. W. Vermeulen. Petra Schwertman is op 6 juni gepromoveerd in Rotterdam op het proefschrift "Quitination in the UV-induced DNA damage response; from proteomics to patient". Promotor: Prof. J. Hoeijmakers; co-promotoren: Dr. W. Vermeulen en Dr. J. Marteijn. Juna de Vries is op 10 juni in Rotterdam gepromoveerd op het proefschrift "Natural course, effects of enzyme therapy and prognostic factors in adults with Pompe disease". Promotor: Prof. van der Ploeg. Erwin Brosens is op 17 juni in Rotterdam gepromoveerd op het proefschrift "Foregut development: an act of balance. Next generation sequencing and copy number variation profiling in EA/TEF". Promotor: Prof. D. Tibboel. Javier Ramirez Martin is op 17 juni in Leiden gepromoveerd op het proefschrift "The cell-type specific role of FcyRIIb in immune-complex-mediated inflammatory diseases". Promotor: Prof. S. van der Maarel; co-promotor: Dr. J. Verbeek. Carine van Capelle is op 18 juni in Rotterdam gepromoveerd op het proefschrift "Children with Pompe disease: clinical characteristics, peculiar features and effects of enzyme replacement therapy". Promotor: Prof. van der Ploeg. Linda van den Berg is op 24 juni in Rotterdam gepromoveerd op het proefschrift "The musculoskeletal system in Pompe disease". Promotor: Prof. van der Ploeg. Celine de Esch is op 25 juni in Rotterdam gepromoveerd op het proefschrift "Therapeutic targets and translational endpoints in fragile X syndrome". Promotor: Prof. R. Willemsen. Joris Deelen is op 25 juni Cum Laude gepromoveerd in Leiden op het proefschrift "Genetic and biomarker studies of human longevity". Promotoren: Prof. P. Slagboom en Prof. R. Westendorp; co-promotor: Dr. M. Beekman. Anine Stam is op 26 juni in Leiden gepromoveerd op het proefschrift "Genetics of migraine and related syndromes". Promotoren: Prof.M. Ferrari en Prof. A. van den Maagdenberg; co-promotor: Dr. G. Terwindt.


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Ralph Stadhouders is in Rotterdam op 12 september gepromoveerd op het proefschrift "Transcription factors, chromatin looping and cellular differentiation; guiding cells towards adulthood". Promotor: Prof. F. Grosveld; co-promotor: Dr. E. Soler. Klaas Hermans is op 16 september gepromoveerd in Rotterdam op het proefschrift "Reflections on the mechanism of DNA mismatch repair". Promotor: Prof. R. Kanaar; co-promotor: Dr. J. Lebbink. Thomas Clapes is op 17 september gepromoveerd in Rotterdam op het proefschrift "Role of CLASP2 in hematopoietic stem cells". Promotor: Prof. E. Dzierzak; co-promotor: Dr. C. Robin. Kasper Derks hoopt op 22 oktober in Rotterdam te promoveren op het proefschrift "The DNA damage respons: nucleic acid regulation in sequence". Promotoren: Prof. J. Hoeijmakers en Prof. B. van der Horst; co-promotor: Dr. J. Pothof. Sherif Shawky Abdou hoopt op 28 oktober in Rotterdam te promoveren op het proefschrift "Development of nanoparticles based assays for the direct detection of unamplified nucleic acids in clinical specimens". Promotor: Prof. F. Grosveld; co-promotor: Dr. H. Azzay. Özge Aydin hoopt in Rotterdam op 29 oktober te promoveren op het proefschrift "Chromatin remodeling in the UV-induced DNA damage response". Promotor: Prof. J. Hoeijmakers; co-promotoren: Dr. W. Vermeulen en Dr. H. Lans. Maikel Wouters hoopt op 12 december in Rotterdam te promoveren op het proefschrift "MicroRNAs, the DNA damage response and cancer". Promotor: Prof. J. Hoeijmakers; co-promotor: Dr. J. Pothof.

Nieuwe medewerkers Bij de afdeling Anatomie & Embryologie (Leiden): Anneloes Dummer is onlangs als OIO gestart op onze afdeling. Oleh Halaidych is ook als OIO begonnen op een project on 'Phenotypic biophysical measurements of disease (hPSC-derived) cardiomyocytes (force, Ca, electrophysiology) and vascular smooth muscle celles

derived from human pluripotent stem cells and the development of new bioassays.

de 'pulmonary vascular development in congenital diaphragmatic hemia".

Bij de afdeling Biochemie (Rotterdam): Ayestha Sijma is per september als OIO gestart in de groep van Peter Verrijzer. Zij gaat werken aan het NWO project "Polycombing chromatin and beyond" to understand the role of protein (de)ubiquitylation by Polycomb group (PcG) proteins in balancing cell differentiation and proliferation. In de groep van Tokameh Mahmoudi zijn twee nieuwe OIO's gestart: Matteusz Stoszo per 1 februari en Enrico Ne per 15 juni.

Bij de afdeling Klinische Genetica (Rotterdam): Tjakko van Ham started on May 1st as a researcher (Marie Curie & ZonMW VENI project "Immune responses in neurodegenerative diseases: Protection or progression?") on the role of the immune system in brain disease. Immune cells are implicated in nearly all brain diseases, but their role is poorly understood. He uses zebrafish as a model system to investigate how immune cells contribute to brain disease or tissue reapir and to figure out how this is controlled molecularly using functional genetics and small molecule screening. Nynke Oosterhof started on July 1st as OIO in the group of Tjakko van Ham. She is interested in using zebrafish to study the role of the immune system in brain diseases and applying new technologies including intravital imaging an RNAseq the brain's immune cells, such as microglia, and what role these cells play in disease. Helen de Boer is per 15 april 2014 als analist begonnen. Laura Kuil is per 1 september gestart als OIO en zal ook gaan werken aan Zebravis neurodegeneratie. Kyra Smit is per 15 september als OIO gestart en werkt aan "Micro RNAs in uveal melanoma).

Bij de afdeling Genetica (Rotterdam): On September 1st, Jana Slyskova started working as a postdoc in the lab of Wim Vermeulen, funded by an EMBO fellowship. She will be screening for synthetic genetic interactions in colorectal cancer.

Bij de afdeling Humane Genetica (Leiden): Remko Goossens (groepsleider Silvère van der Maarel) is per 1 september werkzaam als OIO op het project ‘De rol van een nieuwe chromatine modifier in de pathogenese van FSHD’, gesubsidieerd door het Prinses Beatrix Spierfonds. Haoyu Wu (groepsleider Silvère van der Maarel / Lucia Clemens Daxinger) werkt sinds 1 september (onder de directe leiding van Lucia) als OIO aan epigenetische modificaties in de hersenen in relatie tot mentale retardatie en andere neuroontwikkelingsstoornissen. Rob van den Akker (groepsleider Silvère van der Maarel) werkt als researchanalist aan de opheldering van het epigenetische mechanisme dat ten grondslag ligt aan FSHD en maakt hierbij gebruik van humane cellulaire en muismodel systemen.

Bij de afdeling Kindergeneeskunde (Rotterdam): In de groep van Robbert Rottier is Evelien Eenjes aan een OIO traject begonnen. In diezelfde groep is Daphne Mous al eerder van start gegaan met haar onderzoek naar


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Bij de afdeling Moleculaire Epidemiologie (Leiden): Niels van den Berg is per 1 september aangenomen als OIO op het project "Genes, Germs and Resources. The role of the family in survival since 1812". Voor dit interdisciplinaire project werken sociaaleconomische historici van de Radboud Universiteit Nijmegen samen met epidemiologen van de sectie Moleculaire Epidemiologie van het LUMC. Er wordt onderzoek gedaan naar de invloed van familiale factoren op vroege sterfte van zuigelingen en kinderen en op uitzonderlijke langlevendheid in Nederland van 1812 tot 2015. Dit gebeurt vanuit een innovatief interpretatiekader waarin de gelijktijdige invloeden worden bekeken van

de genetische factoren (genes), de ziekteomgeving (germs) en de sociaaleconomische en culturele aspecten van het individu (resources). Het effect van deze factoren wordt onderzocht met behulp van een multi-generationele benadering waarbij families worden gevolgd over een periode van twee eeuwen. Het doel daarbij is om de wisselwerking op te sporen tussen enerzijds de biologische en genetische invloeden die familieleden met elkaar delen en anderzijds de sociaal-structurele component, bijvoorbeeld de sociale en economische groep die gezinnen en families gemeen hebben. Deze interactie wordt bestudeerd binnen de epidemiologische context van de 19e en 20ste eeuw. Niels gaat o.a. grote historische databestanden analyseren waarbij de levensduur van verschillende groepen individuen over generaties heen gevolgd en vergeleken wordt.

Bij de afdeling Toxicogenetica/Humane Genetica (Leiden): Remco Derr is per Juni begonnen als analist in de groep van Harry Vrieling. Hij gaat samen met Giel Hendriks werken aan de verdere validatie van de ToxTracker assay en het creëren van nieuwe reporter systemen voor verschillende cellulaire stress response pathways. As of September Jenny Singh has started as a PhD student on an ERC-funded project in the group of Haico van Attikum. She will identify and characterise chromatin-modifying enzymes involved in the DNA damage response. In mei is Yvonne Tiersma analiste in het lab van Niels de Wind. Zij werkt onder begeleiding van Mark Drost en in samenwerking met labs uit Nederland, Denemarken en de Verenigde Staten aan een project gefinancierd door de National Institute of Health. Doel van het project is de ontwikkeling van een gestandaardiseerde procedure om de pathogeniciteit te bepalen van varianten in mismatch herstellende genen in patiënten verdacht van Lynch syndroom.

Lezingen/symposia NKI Seminars are given at the NKI, Plesmanlaan 121, Amsterdam: Location: Piet Borst Auditorium, 11.00 hrs. September 12: Emile Voest "The spleen as a key regulator of chemoresistance". September 19: Simon Boulton "Genome stability and the control of homologous recombination". September 24: André Nussenzweig "Determinants of genome integrity in BRCA1/2 mutant cells" (NB: 14:00 hrs) September 26: Wim Vermeulen "Lesionstalled transcription and chromatin remodeling". October 3: Erik Sahai "Imaging invasion and therapy failure". October 17: Adrian Bird "CpG as a genomic signalling module". October 28: Zena Werb "New insights into microenvironmental regulation of breast cancer metastasis". (NB: 10:00 hrs). October 31: Wendy Bickmore "Spatial Genome organisation and gene regulation". November 7: Eva van Rooij "MicroRNA function in cardiac disease". November 21: Kim Nasmyth "What holds chromosomes together". November 28: Jan-Paul Medema "Colon cancer heterogeneity". December 5: Maarten van Lohuizen "Role of Polycomb repressors in stem cells, cancer and development". December 12: Carlos Caldas "Breast cancer: moving on from intrinsic subtypes to a genome driver-based classification". January 16: Reinhard Dummer. January 23: Yitzhak Pilpel. January 30: Luis Blanco February 6: Anja Groth "Chromatin replication and epigenome maintenance". March 27: Roger Greenberg. April 17: Nicholas Dyson. Further info at www.nki.nl Seminars in the lecture series Frontiers in Science in the low countries:

Bij de afdeling Pathologie (Leiden):


Noel de Miranda is gestart als postdoc op het door de MLDS gesubsidieerde project "Identifying mutations in novel DNA Repair genest hat cause familial colorectal cancer".

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September 23: Prof.dr. P. van der Spek, Bioinformatics October 21: Dr. F. Hoebeek, Neuroscience November 18: Dr. W. Baarends, Reproduction and Development January 20: Dr. J. Marteijn, Genetics February 17: Dr. T. Mahmoudi, Biochemistry March 17: Dr. T. van Ham, Clinical Genetics April 21: Dr.ir. N. Galjart, Cell Biology. These lectures are given at Erasmus MC on Tuesdays from 16.00 – 17:00 uur, with drinks afterwards to animate discussions. Further info at http://intranet.erasmusmc.nl/biomedicalscie nce/lectures/agenda.

Sectie 'DNA herstel-mechanismen' De volgende bijeenkomst zal plaatsvinden op vrijdag 7 november in Leiden, LUMC, aanvang 9.30 uur. Deze sectie komt ca. 1 x per 2 maanden bijeen op een vrijdagochtend, alternerend in Leiden en Rotterdam. Coördinatoren: Haico van Attikum (: 071-5269624) en Wim Vermeulen (: 010-7043194).

Sectie ‘Lysosomal Storage Diseases’ Eens per week overleggen betrokkenen van de afdelingen Kindergeneeskunde, Klinische Genetica, Neurologie, Interne Geneeskunde, Ziekenhuis Apotheek en andere afdelingen van het Erasmus MC over de lopende zaken wat betreft patiëntenzorg en onderzoek aangaande lysosomale stapelingsziekten. Hierbij staat de toepassing van enzymvervangingstherapie en daaraan gerelateerd onderzoek centraal (ziekte van Pompe, ziekte van Hurler, ziekte van Hunter en MaroteauxLamy). De bijeenkomsten worden gehouden in het Sophia kinderziekenhuis, Dr Molewaterplein 60, Rotterdam. Voor meer informatie kunt U terecht bij Pim Pijnappel: 0107043357; [email protected].

Verkregen subsidies Danielle Majoor-Krakauer (Klinische Genetica, EMC) heeft van de Stichting Lijf en Leden een grant ontvangen voor haar


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project "Genes, molecular mechanisms and risk prediction for abdominal aortic aneurysm (AAA)". AAA is highly prevalent in the population above the age of 65 years. Since targeted ultrasound screening of persons at high risk allows reduction of AAA related mortality, a risk prediction model based on clinical characteristics and biomarkers is needed to identify timely the persons at risk. We aim to find molecular markers for AAA by identifying genes, pathways and cellular mechanisms involved in remodeling of the vascular wall of the aorta in AAA. In collaboration with the departments of vascular surgery and genetics, a large study cohort of patients, including >100 families with multiple affected individuals, was constructed allowing DNA, RNA and tissue analysis of patients. Which are used together with mouse and human cellular models to identify underlying pathways and molecular mechanisms predisposing to AAA. Grazia Mancini (Klinische Genetica, EMC) heeft een Erasmus Grant ontvangen voor haar onderzoek "Cilia-related defects in brain developmental disorders". Dr. Mandemakers (Klinische Genetica, EMC) heeft een subsidie ontvangen van het Erasmus MC voor zijn promotietraject "Neuronal differentiation of human fibroblast derived iPSCs as a model system for Parkinson’s disease". Jurgen Marteijn (Genetica, EMC) heeft een VIDI beurs toegekend gekregen. Hij neemt DNA reparatie onder de loep: "DNA schade verstoort transcriptie. Hierdoor kunnen cellen sneller doodgaan, wat kan leiden tot versnelde veroudering. We besturende, met geavanceerde microscoop- en eiwitanalyses, in levende cellen de werking van eiwitten betrokken bij reparatie van deze DNA schade". Christine Mummery (Anatomie & Embryologie, LUMC) heeft samen met Dr. P. Passier en Dr. S. Braam (Pluriomics) de Hugo van de Poelgeest prijs ontvangen voor 'Animal Alternatives' (15k euro). Louise van der Weerd (Humane Genetica, LUMC) heeft een NWO VIDI subsidie gehonoreerd gekregen voor haar onderzoek. Beschadigde bloedvaten in het brein en eiwitophopingen in de

hersenvaten kunnen hersenbloedingen veroorzaken. Met beeldvormende technieken zoals MRI wordt bekeken hoe dit proces verloopt en welke bestaande geneesmiddelen zouden kunnen helpen om de eiwitophopingen te verminderen of de bloedvaten sterker te maken.

Personalia/Prijzen Vincenzo Bonifati (Klinische Genetica, EMC) heeft op 11 april zijn inaugurele rede uitgesproken getiteld "Unravelling the Parkinson's code". Op vrijdag 16 mei 2014 heeft Leon Mullenders officieel afscheid genomen als hoofd van de afdeling Toxicogenetica (LUMC). Ter ere van zijn afscheid was het dagsymposium 'DNA damage response and human disease, Nucleotide Excision Repair over the ages' georganiseerd in museum Naturalis, waar bevriende collega's uit binnen- en buitenland spraken over hun werk en de samenwerking met Mullenders.

"Humane Genetica, in het bijzonder de moleculaire en functionele genetica van cystenieren". Marije Meuwissen heeft de Young Investigator Award van de European Society of Human Genetics gewonnen. Wim Vermeulen (Genetica, EMC) is per 1 september door het Trustfonds van de Erasmus Universiteit benoemd tot bijzonder hoogleraar "Genetische Stabiliteit". Silvère van der Maarel heeft op 4 september de Prinses Beatrix Spierfonds Wetenschapsprijs uitgereikt gekregen tijdens de voorstelling 'Free to move' in het Lucenta Danstheater te Den Haag. Van der Maarel heeft de prijs van 1 miljoen euro gekregen voor zijn baanbrekende onderzoek naar de erfelijke spierziekte FSHD, facioscapulohumerale dystrofie.

Foto: Frank van Beek

Overige mededelingen 

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Rob Willemsen (Klinische Genetica, EMC) heeft op 23 mei zijn inaugurele rede uitgesproken getiteld "De verwondering begrijpen". Dorien Peters (Humane Genetica, LUMC) is per 1 juni benoemd tot hoogleraar


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Met ingang van 1 juli is de afdeling Toxicogenetica (LUMC) geïntegreerd in de afdeling Humane Genetica (LUMC). Prof. Silvère van der Maarel is hoofd van deze grote onderzoeksafdeling. Deze zomer is Toxys van start gegaan. Dit spin-off bedrijf van het LUMC test nieuwe stoffen op kankerverwekkende eigenschappen. “Daarvoor gebruiken we onze ToxTracker assay, een systeem dat gebruik maakt van stamcellen”, vertelt directeur dr. Giel Hendriks (Humane Genetica, LUMC). Uniek hieraan is dat het niet alleen laat zien dat een stof kankerverwekkend is, maar ook hoe dat komt.

Minder proefdieren “Farmaceutische en chemische stoffen die met deze nieuwe in vitro-techniek kankerverwekkende eigenschappen blijken te hebben hoeven niet meer in proefdieren getest te worden”, aldus Hendriks. De onderzoeker ontving begin dit jaar een NGI Pre-Seed grant, een subsidie die onderzoekers de mogelijk geeft om een bedrijf te kunnen beginnen. Toxys B.V. maakt op dit moment nog gebruik van de faciliteiten van het LUMC. Hendriks werkt voor 20 procent als onderzoeker bij de afdeling Humane Genetica, de rest van zijn tijd besteedt hij aan Toxys. Mogelijkheden bespreken Heeft u interesse in Toxys? Bekijk de website van Toxys (www.toxys.com) en neem gerust contact op met Giel Hendriks om de mogelijkheden te bespreken, zoals wetenschappelijke samenwerkingen of het gezamenlijk indienen van een subsidie-aanvraag (public-private partnership).

MGC-Bulletin no. 52 Het twee-en-vijftigste MGC Bulletin is gepland voor maart 2015. De sluitingsdatum voor kopij is gesteld op 15 februari 2015. Mededelingen, nieuws, agendapunten en andere wetenswaardigheden gaarne per e-mail inleveren bij Madeleine Nivard of Ingrid Braxhoven, , [email protected]/ [email protected], afdeling Humane Genetica.


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24th MGC-SYMPOSIUM Friday, September 19, 2014 "Engels", Stationsplein 45, Rotterdam Program 24th MGC Symposium 8.45 9.30 9.35 9.55 10.15

10.35

Coffee and registration Opening: Prof.dr. Leon Mullenders Chairman: Prof.dr. Jan Hoeijmakers Simone Olgiatio: "An Exome study of Parkinson's disease in Sardinia, a Meditteranean genetic isolate" (Clinical Genetics, Erasmus MC) Eleonora de Klerk: "Mapping ribosome footprints to investigate translational control during myogenesis" (Human Genetics, LUMC) Parham Solaimani: "An unexpected requirement for Gpr56 revealed by whole transcriptome analysis of endothelial-to-hematopoietic stem cell transition" (Cell Biology, Erasmus MC) Best lecture of the MGC PhD Workshop 2014 Risha Smeding: "Genetic paleo-epidemiology: medically relevant polymorphisms in ancient human populations" (Human Genetics, LUMC)

10.55 11.20 11.40 12.00 12.20

Coffee/tea Chairman: Prof.dr. Bob van de Water Kirsten van Dycke: "Circadian disruption and increased breast cancer risk" (Genetics, Erasmus MC and RIVM) Bas ter Braak: "Mammary gland tumor promotion by chronic administration of different insulin analogues in the p53R270H/+WAPCre mouse model" (LACDR, UL) Kishan Naipal: “Functional ex vivo assay to select homologous recombination deficient breast tumors for PARP inhibitor treatment” (Genetics, Erasmus MC) Robin van Schendel: "Polymerase Theta: stitching genomic wounds at a small expense" (Human Genetics, LUMC)

12.40 -14.00 14.00 14.20 14.40

15.00 15.20

Chairman: Prof.dr. Silvère van der Maarel Tjakko van Ham: "The role of non-neuronal cellular dynamics in neurodegeneration: learning from the zebrafish" (Clinical Genetics, Erasmus MC) Anke Smits: "Optimising the cardiac post-injury response; identifying novel regulators of epicardial EMT" (Molecular Cell Biology, LUMC) Sabine den Hartogh: "Unravelling mesoderm to cardiac progenitor differentiation by using a Mesp1-mCherry-NKX2-5-eGFP dual reporter human embryonic stem cell line (Anatomy and Embryology, LUMC) Guillaume Giraud: "Co-recruitment of Fli-1 and the Ldb1 complex to regulatory sequences of megakaryocytic genes" (Cell Biology, Erasmus MC) Fabrizio Carofiglio: "Zooming-in on chromosomes in mouse meiosis" (Reproduction and Development, Erasmus MC)

15.40 16.10

Lunch

Coffee/tea Chairman: Prof.dr. Frank Grosveld MGC Symposium Lecture: Prof. dr. James Briscoe: "The Gene Regulatory Logic for Reading the Sonic Hedgehog Gradient In The Vertebrate Neural Tube" (MRC National Institute for Medical Research, Developmental Biology, London, UK)

17.10

Drinks and snacks

18.00-23.30

Buffet dinner with musical accompaniment by the Party Band "Go Yellow"


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Abstracts 24th MGC Symposium An Exome study of Parkinson's disease in Sardinia, a Meditteranean genetic isolate Simone Olgiatio Clinical Genetics, Erasmus MC Objectives: We explore the possibility that a considerable proportion of patients from the genetically isolated population of Sardinia are explained by rare variants of strong effect. Background: Parkinson’s disease (PD) is a common neurodegenerative disorder of complex etiology. Rare, highlypenetrant PD-causing mutations and common risk factors of small effect-size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. Methods: We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs leading to missense, nonsense, splice-site changes, or located in 5’- or 3’-UTR regions, that were absent in dbSNP129 and 1000Genomes, and shared by at least 5 unrelated patients (n= 3,881 SNPs) were prioritized and genotyped in 500 independent Sardinian individuals (242 PD and 258 controls). Variants associated with PD with nominal p-value <0.5, and those with odds-ratio >3 (n=155) were validated by Sanger sequencing, yielding 26 SNPs, that were then typed in a replication sample of 2,965 patients and 2,678 controls from Italy, Spain and Portugal. Results: We identified novel moderately-rare variants in several genes that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD. Although no variants achieved genome-wide significance after Bonferroni correction, these findings represent an important resource for follow-up studies. Conclusions: Our study suggests that the genetic bases of PD are highly heterogeneous, with implications for designing future large-scale exome or whole-genome analyses of this disease. Mapping ribosome footprints to investigate translational control during myogenesis Eleonora de Klerk Human Genetics, LUMC The formation of skeletal muscles is associated with drastic changes in protein requirements. These changes are safeguarded by tight control over transcription and mRNA processing. The importance of regulation of mRNA translational for the correct orchestration of myogenesis is currently less clear. Regulation at translational level may affect the abundance and the identity of proteins. Use of alternative translation initiation sites (TISs) in upstream open reading frames (uORFs) may increase or decrease protein synthesis, whereas alternative open reading frames (aORFs) may produce entirely different proteins. We applied ribosome profiling to monitor translation during myogenic differentiation of C2C12 cells. We simplified the existing protocol and developed a dedicated pipeline to identify TISs and quantify translation activity. We identified 5333 unannotated TISs, providing a catalogue of alternative TISs leading to uORFs and aORFs. By comparing ribosome profiling and DeepCAGE data, we found 312 genes that switched to an alternative TIS, which could not be explained by alternative promoter usage. Many of


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these genes were ribosomal protein genes and genes involved in calcium signaling. The same pathways demonstrated discrepant total RNA and ribosome-associated RNA level. Our data therefore suggest that ribosome biogenesis and calcium signaling are most strongly regulated at the translational level, while the majority of differences in protein requirements during myogenesis are ensured by changes at transcriptional level. An unexpected requirement for Gpr56 revealed by whole transcriptome analysis of endothelial-to-hematopoietic stem cell transition Parham Solaimani Cell Biology, Erasmus MC Hematopoietic stem cells (HSCs) are generated via a natural transdifferentiation process known as endothelial-to-hematopoietic cell transition (EHT). Due to small numbers of embryonal arterial cells undergoing EHT and the paucity of markers to enrich for hemogenic endothelial cells, the genetic program driving HSC emergence is largely unknown. Here, we use a highly sensitive RNAseq method to examine the whole transcriptome of small numbers of enriched aortic HSCs, hemogenic endothelial cells and endothelial cells. Gpr56, a G-protein coupled receptor, is one of the most highly upregulated of the 530 differentially expressed genes. Also, highly upregulated are hematopoietic transcription factors, including the ‘heptad’ complex of factors. We show that Gpr56 (mouse and human) is a target of the heptad complex and is required for hematopoietic cluster formation during EHT. Our results identify the processes and regulators involved in EHT and reveal the surprising requirement for Gpr56 in generating the first HSCs. Best lecture of the MGC PhD Workshop 2014 Genetic paleo-epidemiology: medically relevant polymorphisms in ancient human populations Risha Smeding Human Genetics, LUMC Many common deleterious or advantageous phenotypes are known to be caused by or associated with certain genetic variants. Surprisingly enough, we see relatively high frequencies of some deleterious genetic variants in modern populations, associated with diseases like Type II Diabetes or Haemochromatosis. Why is that so? Maybe we are genetically better adapted to different, perhaps more adverse, environmental conditions; conditions like those of our medieval ancestors. Were certain (risk)alleles already present in ancient populations? And if so, at what frequency? Did these frequencies change over time, following the severe environmental changes of recent times? If we want to answer these questions we need to look at the genomes of our ancestors. We have successfully extracted DNA from medieval and post-medieval skeletons from different locations throughout the Netherlands. In order to check for the presence of certain genetic variants in the past, a multiplex SNP-kit was designed typing 23 medically relevant polymorphisms existing of 21 SNPs and 2 indels. Among the targeted polymorphisms are variants associated with or causative for Lactose Tolerance, HIV-resistance, Type II Diabetes, Obesity, Pro-inflammatory response, Coeliac Disease, Cystic Fibrosis, Osteoarthritis, Longevity and Haemochromatosis. Following PCR the short fragments of between 45 and 79bp were sequenced on the Ion PGM Torrent. In order to explore the changes of allele frequencies through time, skeletal remains from different time periods were


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typed (1000-1850 AD). Furthermore a number of modern blood donors from the same region as the medieval skeletons were included for comparison with modern population. In this pilot study we successfully typed medically relevant polymorphisms in 100 (post-) medieval skeletons from two different sites in the Netherlands: Vlaardingen and Eindhoven. The preliminary results show that for a small number of the typed polymorphisms we seem to detect a significant pairwise difference in allele frequency between the ancient and modern populations. Further research, including simulation studies, is required to see if these differences in frequency can be the result of selection. Circadian disruption and increased breast cancer risk Kirsten van Dycke Genetics, Erasmus MC and RIVM

Recent epidemiological studies suggested an association between frequent night shift work and increased breast cancer risk. Possible mechanisms or causal factors are however lacking. Animal studies can provide insight into the causality between circadian rhythm disruption and cancer risk. In contrast to previous studies, which mostly used chemically-induced breast tumors or xenografts, we use the humanized Li-Fraumeni p53R270H/+ WAPCre mouse model. Female p53R270H/+ WAPCre mice spontaneously develop mammary gland tumors (thus mimicking human cancer development), which allows us to study the relationship between circadian rhythm disruption (CRD) and increased breast cancer risk unequivocally. Mice were subjected to chronic circadian disruption (CRD) by exposing them lifelong to weekly alternating light-dark cycles. Li-Fraumeni female mice housed under control normal light dark conditions displayed a tumor latency time of 50.3 weeks, whereas CRD exposed animals (n=25) showed a markedly shortened tumor latency time of 42.6 weeks. In addition, CRD exposed animals showed an increase in body weight compared to the unexposed controls. Bodyweight gain could be explained neither by changes in feed intake nor by alterations in locomotor activity. Within this study, we are the first to provide unequivocal evidence that CRD is a risk factor for breast cancer development. Shift work will remain part of our society and due to the growing 24-hr economy will even increase. Therefore, it is important to understand the molecular mechanisms underlying the chronic adverse health effects induced by CRD, which allows us to develop interventions that at least suppress, and ultimately may prevent the adverse health effects arising from chronic CRD. Currently, we are identifying biomarkers for CRD, which might be helpful in designing intervention strategies. The final goal will be to validate the identified biomarkers in large-scale human cohort studies.


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Mammary gland tumor promotion by chronic administration of different insulin analogues in the p53R270H/+WAPCre mouse model Bas ter Braak LACDR-Toxicology, UL Diabetes is an ever increasing disease which can be treated with insulin analogues, which are chemically modified insulin molecules with improved pharmacokinetic parameters compared to regular human insulin. Insulin analogues may bind both insulin receptors (INSR) as well as the more mitogenic insulin-like growth factor receptors (IGFR). Although these compounds have been tested for carcinogenic side-effects with the standard twoyear in vivo assays in rodents, there are some concerns raised by several epidemiological studies in which an association is suggested between the use of some insulin analogues and the cancer incidence in these diabetic patients. In this study the p53R270H/+WAPCre mouse model was used. These mice have a specific point mutation in the tumor suppressor p53 gene, which corresponds with a hotspot mutation in human tumors. WAPCre ensures selective expression of mutated p53 in the mammary gland and as a result all female mice will develop spontaneous mammary gland tumors. We performed life-long injections of the mice with different insulin analogues: insulin NPH, insulin glargine, insulin X10 (AspB10) or IGF1. We hypothesized that injections with possible carcinogenic insulin compounds would increase the number of tumors that are formed, decrease the latency time for tumor development, or lead to different types or more aggressive tumors. We found that both X10 and IGF1, which both act on the IGFR, significantly decreased the latency time for tumor development (for glargine a slight, nonsignificant effect was observed). A Western blot analysis was done on all primary mammary gland tumors (n=170) to investigate the IR/IGF1R/HER2/ESR/p-Ekt/-p-Akt/ and cadherin status. Hierarchical clustering of this data revealed that X10 and IGF1 induced tumors showed a distinct protein-expression profile that was characterized by high p-Erk levels, suggesting an important role of MAPK signalling cascade in tumor progression/initiation in insulin analogue induced tumors. We further characterized a large subset of these tumors using RNA-sequencing. Gene-expression and mutational profiling will shed light on tumor progression processes and possibly tumor initation. These results indicate a hazard for insulin-analogues with intrinsic mitogenic capacity for the promotion of mammary tumor development. Further evaluation of this hazard in other cancer models as well as understanding the mechanism of this enhanced tumor development will be important for future studies.

Functional ex vivo assay to select homologous recombination deficient breast tumors for PARP inhibitor treatment Kishan Naipal Genetics, Erasmus MC Purpose: Poly(ADP-Ribose) Polymerase (PARP) inhibitors are promising targeted treatment options for hereditary breast tumors with a Homologous Recombination (HR) deficiency caused by BRCA1 or BRCA2 mutations. However, the functional consequence of BRCA gene mutations is not always known and tumors can be HR deficient for other reasons than BRCA gene mutations. Therefore, we aimed to develop a functional test to determine HR activity in tumor samples to facilitate selection of patients eligible for PARP inhibitor treatment. Experimental design: We obtained 54 fresh primary breast tumor


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samples from patients undergoing surgery. We determined their HR capacity by studying the formation of ionizing radiation induced foci (IRIF) of the HR protein RAD51 after ex vivo irradiation of these organotypic breast tumor samples. Tumors showing impaired RAD51 IRIF formation were subjected to genetic and epigenetic analysis. Results: Five out of 45 primary breast tumors with sufficient numbers of proliferating tumor cells were RAD51 IRIF formation deficient (11%, 95%CI: 5%-24%). This HR defect was significantly associated with Triple Negative Breast Cancer (OR:57, 95%CI: 3.9-825, p=0.003). Two out of five HR deficient tumors were not caused by mutations in the BRCA genes, but by BRCA1 promoter hypermethylation. Conclusion: The functional RAD51 IRIF assay faithfully identifies HR deficient tumors and has clear advantages over gene sequencing. It is a relatively easy assay that can be performed on biopsy material, making it a powerful tool to select patients with an HRdeficient cancer for PARP inhibitor treatment in the clinic.

Polymerase Theta: stitching genomic wounds at a small expense Robin van Schendel Human Genetics, LUMC DNA lesions that block replication fork progression are drivers of cancer-associated genome alterations, but the error-prone DNA repair mechanisms acting on collapsed replication are incompletely understood, and their contribution to genome evolution largely unexplored. By whole genome sequencing of animal populations that were clonally propagated for over 50 generations, we identify a distinct class of deletions from 50-300 basepairs that spontaneously accumulate in C. elegans strains lacking translesion synthesis (TLS) polymerases. Emerging DNA double-strand breaks are repaired via an error-prone mechanism in which the outermost nucleotide of one end serves to prime DNA synthesis on the other end. This pathway critically depends on the A-family polymerase theta (θ), which protects the genome against gross chromosomal rearrangements. By comparing the genomes of isolates of C. elegans from different geographical regions, we found that in fact most spontaneously evolving structural variations match the signature of polymerase thetamediated end joining (TMEJ), arguing that TMEJ is an important source of genetic diversification.

The role of non-neuronal cellular dynamics in neurodegeneration: learning from the zebrafish Tjakko van Ham Clinical Genetics, Erasmus MC Many incurable brain diseases, including Alzheimer’s disease, involve activity of the immune system. Although immune responses represent a potential target to treat disease, it is unknown whether and when immune cells are harmful or act protectively. We want to uncover how immune cells, including microglia, the brain’s resident macrophages, respond to cues related to brain disease, and how their activity contributes to recovery or deterioration of brain tissue. Furthermore, to better understand these responses we aim to identify signalling pathways controlling their activity. To study these questions we use the zebrafish. The zebrafish genome, brain and immune system are highly conserved with mammals. Zebrafish larvae are transparent and immune cells can be tracked in vivo with great detail using intravital


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microscopy [1,2]. To elucidate the spatiotemporal immunological events upon neuronal cell death genetically-targeted cell ablation specifically inducing cell death in the nervous system is used, followed by tracking of immune cells by high resolution intravital imaging. Initial clearance of dead neurons occurs by increased numbers of infiltrating macrophages and resident microglia [2,3]. Following clearance of dead neurons, their numbers in the brain decrease by migration, apoptosis and engulfment by microglia, revealing the chronological cellular sequence of resolution of neuroinflammation. Our most surprising finding is that immune cells in the brain undergo apoptosis and are engulfed by microglia. This concept has not previously been described in the brain, and suggests that inflammation in the brain can be resolved in a way similar to a peripheral wounding response, but involving different cell types. Our current studies focus on identifying pathways controlling these immune responses in the brain to help understand and ultimately benefit treatment of human brain diseases.

Optimising the cardiac post-injury response; identifying novel regulators of epicardial EMT Anke Smits Molecular Cell Biology, LUMC Cell-based therapy has been proposed to treat patients after myocardial infarction (MI) in an attempt to replace lost contractile tissue. Cell transplantation studies using progenitor cells with the potential to differentiate into new cardiac tissue have shown to be safe and feasible but the retention of cells is low and the effect on cardiac performance is limited. Therefore the local activation of progenitor cells in the heart itself may be more promising. During development, the epicardium (the outer layer of the heart) is formed from the pro-epicardial organ. Epicardial cells undergo epithelial to mesenchymal transition (EMT) and migrate into the developing myocardium where they differentiate into several cardiac cell types. In the adult heart, the epicardium is quiescent but upon damage it becomes reactivated again resulting in EMT and migration. Epicardial derived cells have been shown to differentiate into cardiomyocytes, showing the potential of these cells as progenitor cells and their ability to participate in cardiac regeneration. In this project we aim to identify novel regulators of epicardial EMT in an attempt to increase the number of epicardial cells participating in the post-injury response.

Unravelling mesoderm to cardiac progenitor differentiation by using a Mesp1mCherry-NKX2-5-eGFP dual reporter human embryonic stem cell line Sabine den Hartogh Anatomy and Embryology, LUMC Human pluripotent stem cells (hPSCs) have the potential to differentiate into any cell type of the human body. This makes the use of hPSCs of interest for regenerative medicine, drug screenings and embryonic development. Several optimized differentiation protocols of hPSCs to cardiomyocytes have been generated, including growth factor directed differentiations as monolayers or as three-dimensional aggregates. Different studies have demonstrated that hPSC-derived cardiomyocytes (hPSC-CMs) faithfully recapitulate the early molecular events during embryonic development. Recently, we have generated a cardiac reporter line in human embryonic stem cells (hESC) by introducing Green Fluorescent Protein (GFP), in the genomic locus of the early cardiac transcription factor


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NKX2-5, which enables us to visualize the derivation of NKX2-5+ cardiomyocytes during in vitro differentiation and purify these cells by Fluorescent Activated Cell Sorting (FACS). Transcription factor Mesp1 is a key regulator of pre-cardiac mesoderm and represents the earliest marker of cardiovascular progenitors. In order to identify early cardiac progenitors and the molecular mechanisms involving their further cardiovascular differentiation in vitro, we generated a MESP1-mCherry-NKX2-5-eGFP hESC -dual reporter line. Cardiac differentiation of MESP1-mCherry-NKX2-5-eGFP hESCs resulted in the transient activation of mCherry expression with a peak at day 3-4, recapitulating mesodermal differentiation. We further show the characteristics of these Mesp1-mCherry expressing cells, and their ability to efficiently differentiate towards the cardiac lineage in the presence of Wnt-pathway inhibitor Xav939. This model allows us to unravel mechanisms that are important for expansion of cardiac mesoderm and the transition to cardiac progenitors and their derivatives. A better understanding of these processes will be beneficial for optimization of differentiation protocols towards specific subtypes of cardiac cells, which will be of high interest for clinical and/or pharmaceutical applications. Co-recruitment of Fli-1 and the Ldb1 complex to regulatory sequences of megakaryocytic genes Guillaume Giraud Cell Biology, Erasmus MC Hematopoiesis is the hierarchical process by which hematopoietic stem cells (HSC) give rise to all mature blood cells through multipotent and oligopotent progenitors. Every differentiation stages are controlled by several signals including transcription factors (TF). These signals end with the activation and the repression of lineage-specific gene expression. We are particularly interested in the transcriptional control of erythropoiesis and megakaryopoiesis. Several TF are involved in the development of both lineages, including Fli-1. This Ets TF is an important protein for the development of megakaryocytes while it represses erythropoiesis. Importantly, its high expression in erythroid progenitors is a recurrent event observed in murine erythroleukemia. However, how Fli-1 works to control these lineages is not clearly understood. By using an NLS-tagged Fli-1 protein in MEL cells (Murine ErythroLeukemia) (where a biotag and a 3xFlag sequences have been integrated close to its NLS (Giraud, NAR, 2014)), we identified several proteins that belong to the Ldb1 complex, an important TF complex involved in both erythropoiesis and megakaryopoiesis. ChIP-Seq data for these proteins revealed the co-recruitment of Fli-1 and the Ldb1 complex to regulatory sequences of megakaryocytic genes whose expression is decreased after Fli-1 repression. Altogether, these data suggest that Fli-1 and the Ldb1 complex cooperate to activate megakaryocyte genes expression and hence, megakaryopoiesis.

Zooming-in on chromosomes in mouse meiosis Fabrizia Carofiglio Reproduction and Development, Erasmus MC

Generation of haploid gametes for sexual reproduction occurs via a process named meiosis which consists of a single DNA replication event followed by two subsequent cell divisions (meiosis I and II). During meiotic prophase I, the replicated genome undergoes homologous recombination (HR) which serves the dual aim of mediating genetic shuffling, to generate a unique genetic set to transfer to the progeny, and of favouring interactions between


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homologous chromosomes. Homologous chromosome pairing and synapsis are in fact essential events to achieve proper meiotic division. In male meiosis, sex chromosomes do not achieve full synapsis due to their extensive heterology. This triggers a silencing mechanism (MSCI) that compartmentalizes the X and Y chromatin, rendering it transcriptionally inactive. Homologous recombination in meiotic cells is triggered by the induction of DNA double-strand breaks (DSBs) by the meiosis-specific transesterase SPO11. Repair of such DSBs via HR requires an intact template for repair which, in meiocytes, can be either the sister chromatid or the homologous chromosome. In order to favour interactions between homologs, DSB repair via the sister chromatid is repressed. As a consequence, the unsynapsed X chromosome shows persistent DSBs even after the autosomes have completed repair of the meiotic DSBs. When SPO11 is not functional and meiotic DSBs are not induced, HR does not take place and homologous chromosome pairing and synapsis are impaired. Despite extensive asynapsis, a silenced chromatin area is still observed which does not always coincide with the X and Y chromosomes. Using a SPO11-inactive mouse model we investigated the role of SPO11 protein and activity in the meiosis-specific events of chromatin silencing, homologous chromosome pairing and synapsis. We also applied state of the art microscopy techniques to study the sites of meiotic DSBs in the context of chromosome organization and DNA repair protein recruitment to the chromosomes.

MGC Symposium Lecture The Gene Regulatory Logic for Reading the Sonic Hedgehog Gradient In The Vertebrate Neural Tube Prof. dr. James Briscoe MRC National Institute for Medical Research, Developmental Biology, London, UK The generation of the correct neuronal subtype at the appropriate position and time in the vertebrate neural tube is the first step in the assembly of functional neural circuits. It also represents one of the best-studied examples of embryonic pattern formation. Distinct neuronal subtypes are generated in a precise spatial order from progenitor cells according to their location along the anterior-posterior and dorsal-ventral axes. Underpinning this organization is a complex network of extrinsic and intrinsic factors. Particularly well understood is the mechanism that determines the generation of different neuronal subtypes in ventral regions of the spinal cord. In this region of the nervous system, the secreted protein Sonic Hedgehog (Shh) acts in graded fashion to organize the pattern of neurogenesis. This is a dynamic process in which increasing concentrations and durations of exposure to Shh generate neurons with successively more ventral identities. Interactions between the receiving cells and the graded signal underpin the mechanism of Shh action. In particular, the regulation of transcription factors induced or repressed by Shh signaling play an essential role in determining the graded response of cells. Thus the accurate patterning of the neural tube and the specification of motor neurons and the other neuronal subtypes characteristic of this region relies on the continuous processing and constant refinement of the cellular response to graded Shh signaling.


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De MGC bestuurders en hun instituten Instituut Celbiologie  010-7043593 Erasmus MC Postbus 2040, 3000 CA Rotterdam hoofd: Prof.dr. D.F.E. Huylebroeck (lid MGC bestuur)

Centrum voor Humane en Klinische Genetica, LUMC  071-5269400 Postbus 9600, 2300 RC Leiden hoofd: Prof.dr. S.M. van der Maarel (lid MGC bestuur)

Instituut Genetica  010-7043199 Erasmus MC Postbus 2040, 3000 CA Rotterdam hoofd: Prof.dr. J.H.J. Hoeijmakers (lid MGC bestuur)

Afdeling Humane Genetica  071-5269600 Leids Universitair Medisch Centrum Postbus 9600, 2300 RC Leiden Prof.dr. L.H.F. Mullenders (voorzitter MGC bestuur)

LACDR/ Toxicology  071-5276223 Faculteit W&N, Universiteit Leiden Postbus 9502, 2300 RA Leiden hoofd: Prof.dr. B. van de Water (lid MGC bestuur)

Instituut Klinische Genetica  010-7043198 Erasmus MC Postbus 2040, 3000 CA Rotterdam hoofd: Prof.dr. R.M.W. Hofstra (secretaris MGC bestuur)

Andere instituten/groepen binnen het MGC Moleculaire Celbiologie, LUMC: (Prof.dr. H.J. Tanke & Prof.dr. A.K. Raap, Prof.dr. J. Noordermeer & Dr. L. Fradkin, Prof.dr. R. Hoeben, Prof.dr. J.A. Maassen en Prof.dr. P. ten Dijke) Neurologie, groep neurogenetica, LUMC (Prof.dr. R.A.C. Roos, Prof.dr. J.J.G.M. Verschuuren en Prof.dr. M.D. Ferrari) Huid- en geslachtsziekten, groep erfelijke melanomen, LUMC (Prof.dr. R. Willemze, Prof.dr. W. Bergman, Dr. F. de Gruijl en Dr. N.A. Gruis) Pathologie: moleculaire tumorpathologie, LUMC (Prof.dr. P.C.W. Hogendoorn, Prof.dr. J. Morreau, Prof. J.V.M.G. Bovee en Prof.dr. P. Devilee) Medische Statistiek: Moleculaire epidemiologie, LUMC (Prof.dr. P.E. Slagboom) Anatomie en Embryologie, LUMC (Prof.dr. C.L. Mummery) Optical Imaging Centre (OIC), Department of Pathology, Erasmus MC (Prof. Dr. A. B. Houtsmuller) Kinderheelkunde, Ontwikkelingsbiologie groep, Erasmus MC (Prof.dr. D. Tibboel) Genetische epidemiologie, Erasmus MC (Prof.dr. C.M. van Duijn) Afd. Voortplanting en Ontwikkeling, Erasmus MC (Prof.dr. J.A. Grootegoed) Forensische Moleculaire Biologie, Erasmus MC (Prof.dr. M. Kayser) Bioinformatica, Erasmus MC (Prof.dr. P. van der Spek) Biochemie, Erasmus MC (Prof.dr. P. Verrijzer) [n.b. verbeteringen voor deze lijst gaarne doorgeven aan het secretariaat]

Het MGC secretariaat is gevestigd op de afdeling Humane Genetica, Leiden.  071-5269600; Fax 071-5268284 Directie secretaris: Dr. M.J.M. Nivard  071-5269605 e-mail: [email protected]


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MGC-Bulletin, Nr. 51, September 2014 In dit nummer:

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