Dr Freek van Eeden

Dr Freek van Eeden Senior Lecturer
Department of Biomedical Science
The University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room: C13 Firth Court
Telephone: +44 (0) 114 222 2348
email: f.j.vaneeden@sheffield.ac.uk

General	Brief career history 2006- present: Senior Lecturer, University of Sheffield 1999 - 2005: Junior Group Leader Hubrecht Laboratory, Utrecht, The Netherlands 1997 - 1999: Post-doctoral worker, D. StJohnston Lab, Wellcome/CRC Inst. Cambridge UK 1992 - 1997: PhD, C. Nüsslein-Volhard Lab. Max Planck Inst. für Entwicklungsbiologie, Tübingen, Germany 1986 - 1992 MSc. Wageningen Agricultural University, The Netherlands Research interests Using the zebrafish as a genetic tool to study development and disease. We are interested in understanding the role of the patched genes in Hedgehog signaling. In addition, we have created a knockout for the von Hippel Lindau disease (VHL) gene and are interested in modeling VHL deficient cancers in zebrafish. Professional activities Invited teacher at regular EMBO courses at the MPI in Tübingen (recently also Sheffield) Presenter at open science days and public lectures in Utrecht/Wageningen International collaboration on TILLING with Hubrecht Laboratory Utrecht/Sanger Inst. Cambridge Invited speaker at: ZDM8, Boston, Aug 2015; Zebrafish PI Meeting Ein gedi 2014; BSDB meeting 2013; European zebrafish meeting Barcelona 2013 Reviewer for: BBSRC, Development, FNRS, Swiss research council, Singapore, Hong-Kong and many others Full publications
Research	Disease modelling in zebrafish Understanding VHL and hypoxic signalling in Cancer The zebrafish provides a powerful organism to model human development and disease. We are exploiting and developing the zebrafish, e.g. by creating such disease models, by using knockout technology like CRISPR, or by looking for chemicals that can modify disease-relevant phenotypes. One of our current projects, models the human Von Hippel Lindau disease, caused by mutation of the VHL gene. VHL is a negative regulator of the Hypoxia Inducible Factor (HIF) signalling pathway, which is vital for development and survival of many tumours. However, this is not the only function of VHL and over the years numerous others have been identified. We found that in zebrafish, the functions of human VHL have been split over two genes, which we named vhl and vhl-like (vll). Interestingly, we found that the fish vhl gene has an important role in HIF regulation, as mutants we made by reverse genetics show all hallmarks of an inappropriate hypoxic response under normoxic conditions. The role of vll was initially enigmatic, null mutants that we created in this gene were viable and fertile. However, using a unique and novel in vivo reporter for genome stability that we created, we discovered that the vll gene is important for maintaining genome stability, which is a major driver for tumour initiation. This is what we are currently trying to understand better. Current collaborations: Sherif El-Khamisy (genome stability), Albert Ong (pkd2 model), Jane McKeating (Birmingham), Francesco Argenton (Padua) (both glucocorticoid-HIF interaction). Funding EU FP7 EU Trancyst HEFCE
Teaching	Undergraduate and postgraduate taught modules Undergraduate: BMS109 Lab Skills & Skills Sessions BMS110 Research Topics in Biomedicine BMS242/243 Principles of Developmental Biology BMS243/247 Stem Cells BMS336 Modelling Human Disease and Dysfunction Level 3 Practical and Dissertation Modules Masters (MSc): BMS6083 Practical Developmental Genetics (Co-ordinator)

General

Brief career history

2006- present: Senior Lecturer, University of Sheffield
1999 - 2005: Junior Group Leader Hubrecht Laboratory, Utrecht, The Netherlands
1997 - 1999: Post-doctoral worker, D. StJohnston Lab, Wellcome/CRC Inst. Cambridge UK
1992 - 1997: PhD, C. Nüsslein-Volhard Lab. Max Planck Inst. für Entwicklungsbiologie, Tübingen, Germany
1986 - 1992 MSc. Wageningen Agricultural University, The Netherlands

Research interests

Using the zebrafish as a genetic tool to study development and disease. We are interested in understanding the role of the patched genes in Hedgehog signaling. In addition, we have created a knockout for the von Hippel Lindau disease (VHL) gene and are interested in modeling VHL deficient cancers in zebrafish.

Professional activities

Invited teacher at regular EMBO courses at the MPI in Tübingen (recently also Sheffield)
Presenter at open science days and public lectures in Utrecht/Wageningen
International collaboration on TILLING with Hubrecht Laboratory Utrecht/Sanger Inst. Cambridge
Invited speaker at: ZDM8, Boston, Aug 2015; Zebrafish PI Meeting Ein gedi 2014; BSDB meeting 2013; European zebrafish meeting Barcelona 2013
Reviewer for: BBSRC, Development, FNRS, Swiss research council, Singapore, Hong-Kong and many others

Full publications

Research

Disease modelling in zebrafish

Understanding VHL and hypoxic signalling in Cancer

The zebrafish provides a powerful organism to model human development and disease. We are exploiting and developing the zebrafish, e.g. by creating such disease models, by using knockout technology like CRISPR, or by looking for chemicals that can modify disease-relevant phenotypes.

One of our current projects, models the human Von Hippel Lindau disease, caused by mutation of the VHL gene. VHL is a negative regulator of the Hypoxia Inducible Factor (HIF) signalling pathway, which is vital for development and survival of many tumours. However, this is not the only function of VHL and over the years numerous others have been identified. We found that in zebrafish, the functions of human VHL have been split over two genes, which we named vhl and vhl-like (vll).

Interestingly, we found that the fish vhl gene has an important role in HIF regulation, as mutants we made by reverse genetics show all hallmarks of an inappropriate hypoxic response under normoxic conditions. The role of vll was initially enigmatic, null mutants that we created in this gene were viable and fertile. However, using a unique and novel in vivo reporter for genome stability that we created, we discovered that the vll gene is important for maintaining genome stability, which is a major driver for tumour initiation. This is what we are currently trying to understand better.

Current collaborations: Sherif El-Khamisy (genome stability), Albert Ong (pkd2 model), Jane McKeating (Birmingham), Francesco Argenton (Padua) (both glucocorticoid-HIF interaction).

Funding

EU FP7
EU Trancyst
HEFCE

Teaching

Undergraduate and postgraduate taught modules

Undergraduate:

BMS109 Lab Skills & Skills Sessions
BMS110 Research Topics in Biomedicine
BMS242/243 Principles of Developmental Biology
BMS243/247 Stem Cells
BMS336 Modelling Human Disease and Dysfunction
Level 3 Practical and Dissertation Modules

Masters (MSc):

BMS6083 Practical Developmental Genetics (Co-ordinator)

Selected publications

Journal articles

Vettori A, Greenald D, Wilson GK, Peron M, Facchinello N, Markham E, Sinnakaruppan M, Matthews LC, McKeating JA, Argenton F & van Eeden FJM (2017) Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization. Proceedings of the National Academy of Sciences, 114(37), 9948-9953.
Wilkinson RN, Elworthy S, Ingham PW & van Eeden FJM (2017) Fin clipping and genotyping embryonic zebrafish at 3 days post-fertilization. BioTechniques, 62(1). View this article in WRRO
Greenald D, Jeyakani J, Pelster B, Sealy I, Mathavan S & van Eeden FJ (2015) Genome-wide mapping of Hif-1α binding sites in zebrafish. BMC Genomics, 16(1). View this article in WRRO
Wilkinson RN, Elworthy S, Ingham PW & van Eeden FJM (2013) A method for high-throughput PCR-based genotyping of larval zebrafish tail biopsies.. Biotechniques, 55(6), 314-316.
Watson O, Novodvorsky P, Gray C, Rothman AMK, Lawrie A, Crossman DC, Haase A, McMahon K, Gering M, Van Eeden FJM & Chico TJA (2013) Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling.. Cardiovasc Res, 100(2), 252-261. View this article in WRRO
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 et al (2013) A systematic genome-wide analysis of zebrafish protein-coding gene function.. Nature, 496, 494-497. View this article in WRRO
Santhakumar K, Judson EC, Elks PM, McKee S, Elworthy S, van Rooijen E, Walmsley SS, Renshaw SA, Cross SS & van Eeden FJM (2012) A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis.. Cancer Res, 72(16), 4017-4027.
Elks PM, van Eeden FJ, Dixon G, Wang X, Reyes-Aldasoro CC, Ingham PW, Whyte MKB, Walmsley SR & Renshaw SA (2011) Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model.. Blood, 118(3), 712-722.
van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, Kane DA , Kelsh RN et al (1996) Mutations affecting somite formation and patterning in the zebrafish, Danio rerio.. Development, 123, 153-164.