Dr Freek van Eeden
Room: C13 Firth Court
Brief career history
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.
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).
Undergraduate and postgraduate taught modules
- 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.