Sheffield Institute for Nucleic Acids

Dr Freek van Eeden

Research Interests

Dr van Eeden has worked in the area of disease modeling in zebrafish for the last 17 years. He participated in a pioneering genetic screen that established the zebrafish as a vertebrate model for development and disease, and he has been contributing to development of the zebrafish system ever since. A main interest in the lab is to understand Von Hippel Lindau disease. This disease leads to formation of a variety of tumours in human patients but the precise reason for this is still poorly understood. His lab has modelled this disease in zebrafish by creating knockouts in both orthologs of VHL in fish. These genes, named vhl and vhl-like, appear to have diversified their function; vhl being a dominant regulator of hypoxia inducible factor. vhl-like, surprisingly, has a function in DNA repair. The latter function was discovered to due to the fortuitous establishment of an in vivo GFP reporter system for genome stability. Use of this reporter system has allowed his lab to define a complex, and dual role of the vhl-type genes in DNA repair. In order to place these DNA repair defects with respect to the known pathways and to study potential interactions, we have used CRISPR to create a collection of mutants with defects in DNA repair including brca2, rad52, rad51 and others. Furthermore, we are developing protocols to damage DNA in various ways and developing analysis methods. We envisage that the use of embryos rather than cell lines, which are often tumor derived or culture adapted, may help to compare and define the roles of these genes. We are collaborating with Dr El-Khamisy and Bryant on this project. In addition, in collaboration with Dr El-Khamisy we have helped to develop a zebrafish CRISPR model for SCAN1 and AT, two neurodegenerative diseases caused by defective DNA repair. Altogether, we are creating an extremely powerful, genetically amenable model system for in vivo analysis of DNA repair and their links with tumourigenesis, neurodegeneration, and aging.


Publications

  • Vettori A, Greenald D, Wilson GK, Peron M, Facchinello N, Markham E, Sinnakaruppan M, Matthews LC, McKeating JA, Argenton F, van Eeden FJM. Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization. Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):9948-9953.
  • Kim HR, Greenald D, Vettori A, Markham E, Santhakumar K, Argenton F, van Eeden F. Zebrafish as a model for von Hippel Lindau and hypoxia-inducible factor signaling. Methods Cell Biol. 2017;138:497-523.
  • Greenald D, Jeyakani J, Pelster B, Sealy I, Mathavan S, van Eeden FJ. Genome-wide mapping of Hif-1α binding sites in zebrafish. BMC Genomics. 2015 Nov 11;16:923.
  • Wilkinson RN, Elworthy S, Ingham PW, van Eeden FJ. A method for high-throughput PCR-based genotyping of larval zebrafish tail biopsies. Biotechniques. 2013 Dec;55(6):314-6.
  • Watson O, Novodvorsky P, Gray C, Rothman AM, Lawrie A, Crossman DC, Haase A, McMahon K, Gering M, Van Eeden FJ, Chico TJ. Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxicsignalling. Cardiovasc Res. 2013 Nov 1;100(2):252-61.
  • Basten SG, Davis EE, Gillis AJ, van Rooijen E, Stoop H, Babala N, Logister I, Heath ZG, Jonges TN, Katsanis N, Voest EE, van Eeden FJ, Medema RH, Ketting RF, Schulte-Merker S, Looijenga LH, Giles RH. Mutations in LRRC50 predispose zebrafish and humans to seminomas. PLoS Genet. 2013 Apr;9(4):e1003384
  • Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E, van Eeden F, Sealy I, White RJ, Herd C, Nijman IJ, Fényes F, Mehroke S, Scahill C, Gibbons R, Wali N, Carruthers S, Hall A, Yen J, Cuppen E, Stemple DL. A systematic genome-wide analysis of zebrafish protein-coding gene function. Nature. 2013 Apr 25;496(7446):494-7.
  • Santhakumar K, Judson EC, Elks PM, McKee S, Elworthy S, van Rooijen E, Walmsley SS, Renshaw SA, Cross SS, van Eeden FJ. A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis. Cancer Res. 2012 Aug 15;72(16):4017-27.
  • Sapetto-Rebow B, McLoughlin SC, O’Shea LC, O’Leary O, Willer JR, Alvarez Y, Collery R, O’Sullivan J, Van Eeden F, Hensey C, Kennedy BN. Maternal topoisomerase II alpha, not topoisomerase II beta, enables embryonic development of zebrafish top2a-/- mutants. BMC Dev Biol. 2011 Nov 23;11:71.
  • Elks PM, van Eeden FJ, Dixon G, Wang X, Reyes-Aldasoro CC, Ingham PW, Whyte MK, Walmsley SR, Renshaw SA. Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood. 2011 Jul 21;118(3):712-22.
  • van Rooijen E, Voest EE, Logister I, Bussmann J, Korving J, van Eeden FJ, Giles RH, Schulte-Merker S. von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish. Dis Model Mech. 2010 May-Jun;3(5-6):343-53.
  • van Rooijen E, Voest EE, Logister I, Korving J, Schwerte T, Schulte-Merker S, Giles RH, van Eeden FJ. Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood. 2009 Jun 18;113(25):6449-60. Zebrafish as a model for von Hippel Lindau and hypoxia-inducible factor
Dr Freek van Eeden
Senior Lecturer
Department of Biomedical Science
+44 (0)114 271 2348
f.j.vaneeden@sheffield.ac.uk