Home| Professor of Cellular and Molecular Biology |
Contact details:
| Tel: | +44 20 7882 2275 |
| Fax: | +44 20 7882 2183 |
| Email: | d.nizetic@qmul.ac.uk |
| Address: | Centre for Paediatrics, |
Biography
Dean Nizetic was born in Split , Croatia in 1959. He obtained his M.D. at the Faculty of Medicine, University of Zagreb , Croatia , in 1982. He received the Max-Planck Stipendium and performed the experimental work used for his PhD thesis in Molecular Biology at the Max-Planck-Institute for Biology in Tuebingen , Germany , obtained the PhD in 1987 from Unversity of Belgrade. He was a Research Fellow at the Imperial Cancer Research Fund laboratories at Lincoln 's Inn Fields, in the Genome Analysis Department (1987-1994). From 1994, he is an independent research group leader at Centre for Applied Molecular Biology, School of Pharmacy , University of London where starting as a Lecturer in 1994, becomes a Senior Lecturer in 1996 and a Reader in 2000. From July 2001, he obtained a Chair in Cellular and Molecular Biology at Barts and The London School of Medicine, Queen Mary, University of London .
Research Activity
The long term research theme of Prof. Nizetic's group is the study of chromosome and gene dose effects (aneuploidy and haploinsufficiency) on cellular functions, specifically the phenotypic features of Down syndrome (DS), caused by just one extra copy of perfectly normal, chromosome 21. The homeostasis of cellular proteins is significantly disturbed by an overdose of chromosome 21 genes and non-genic functional elements, causing multiple effects through poorly understood mechanisms: fewer (neuronal) cells are formed, they form fewer and hypo-functional synapses, neurons undergo compulsory Alzheimer's degeneration extremely early in life, heart endothelial cushion cells fail to close the septum, cells are much more resistant to dividing out of control and becoming cancer cells, the latter is true for most tissues except some haematopoietic lineages and spermatogonia, which are more prone to malignancy. From these facts, it is clear that much could be learned about cell proliferation, cell differentiation, neurodegeneration, and the protection from cancer, by identifying the molecular pathways and proteins which are altered by trisomy 21.
Prof. Nizetic is one of the world leading scientists in research into DS-associated leukaemia, holder of the programme grant and prestigious Gordon Piller PhD studentship from Leukaemia Research Fund. Besides this, the lab recently participated in the generation of a unique mouse model for DS, the first mouse to contain the human chromosome 21. This mouse model (article in Science of September 23 rd 2005 ) represents a major scientific breakthrough in research into aneuploidies, and has been chosen by Guardian science commentators as the worldwide number one scientific breakthrough for 2005. Currently, Prof. Nizetic's research focuses on aneuploidy research using this model and mouse embryonic stem cells.
The long term research theme of Prof. Nizetic's group is the study of chromosome and gene dose effects (aneuploidy and haploinsufficiency) on cellular functions, specifically the phenotypic features of Down syndrome (DS). Prof. Nizetic is one of the world leading scientists in research into DS-associated leukaemia, holder of the programme grant and prestigious Gordon Piller PhD studentship from Leukaemia Research Fund. These projects involve the use of mouse embryonic stem cells for in vitro differentiation to erythroid/megakaryocytic lineages, as a cellular model for the study of pathogenesis of childhood leukaemia associated with DS.
Nizetic lab recently participated in the generation of a unique mouse model for DS, the first mouse to contain the human chromosome 21 (HSA21). This mouse model (article in Science of September 23 rd 2005) represents a major scientific breakthrough in research into aneuploidies, and has been chosen by Guardian science commentators as the worldwide number one scientific breakthrough for 2005. Currently, Prof. Nizetic's research focuses on aneuploidy research using this model and mouse embryonic stem (ES) cells. Prof. Nizetic is co-coordinating a workpackage within the 12M€ EU-FP6- Integrated Project called "AnEUploidy: understanding the importance of gene dosage imbalance in human health using genetics, functional genomics and systems biology". The workpackage co-coordinated by Prof. Nizetic within the AnEUploidy consortium is called "Gene dosage imbalance in embryonic stem cells". The goal of this workpackage is to exploit the unique advantages of the embryonic stem (ES) cell as an experimental paradigm to identify the effects of gene dosage imbalance on the global transcriptome and proteome. The main advantages are in overcoming the problem of variability of transcriptome and proteome due to differences in the human population, mouse inter-strain variability, and tissue sampling and processing. Furthermore, dosage imbalance effects on the ability of pluripotent ES cells to differentiate into lineages relevant to human aneuploidy phenotypes will also be investigated. This approach will allow us to study if ES cells, transchromosomic for a whole extra human chromosome 21, show delayed or abnormal differentiation into neuronal, cardiac, haematopoietic and other cell lineages. Furthermore, these effects could then be assigned to specific segments of HSA21, groups of genes, and eventually single genes, establishing protocols and assays for development of novel therapeutic approaches.
Key Publications
• Serena De Vita, Claudia Canzonetta, Claire Mulligan, Frederic Delom, Jurgen Groet, Chiara Baldo, Lesley Vanes, Franca Dagna-Bricarelli, Alex Hoischen, Joris Veltman, Elizabeth M. C. Fisher, Victor L.J. Tybulewicz and Dean Nizetic. Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down Syndrome. Oncogene In Press, 2010.
• 2. Louise Reynolds, Alan Watson, Marianne Baker, Tania Jones, Gabriela D'Amico, Stephen Robinson, Carine Joffre, Sarah Garrido-Urbani, Juan Carlos Rodríguez-Manzaneque, Michel Aurrand-Lions, Denise Sheer, Franca Dagna-Bricarelli, Dean Nizetic, Christopher McCabe, Andrew Turnell, Stephanie Kermorgant, Beat Imhof, Elizabeth Fisher, Victor Tybulewicz, Ralf Adams, Ian Hart, Estefania Martino-Echarri and Kairbaan Hodivala-Dilke. Tumour angiogenesis is reduced in the Tc1 mouse model of Down Syndrome.
Nature Jun 10;465(7299):813-7 (2010).
• Kate Alford, Amy Slender, Lesley Vanes, Zhe Li, Elizabeth M. C. Fisher, Dean Nizetic, Stuart H. Orkin, Irene Roberts, and Victor L. J. Tybulewicz. Perturbed hematopoiesis in the Tc1 mouse model of Down Syndrome. Blood Apr 8;115(14):2928-37, 2010.
• Wang Y, Mulligan C, Denyer G, Delom F, Dagna-Bricarelli F, Tybulewicz VL, Fisher EM, Griffiths WJ, Nizetic D, Groet J. Quantitative proteomic characterisation of a mouse embryonic stem cell model of down syndrome. Mol Cell Proteomics (4):585-95 (2009).
• Claudia Canzonetta, Claire Mulligan, Samuel Deutsch, Sandra Ruf, Aideen O’Doherty, Robert Lyle, Christelle Borel, Nathalie Lin-Marq, Frederic Delom, Jürgen Groet, Felix Schnappauf, Serena De Vita, Sharon Averill, John V. Priestley, Joanne E Martin, Janet Shipley, Gareth Denyer, Charles J. Epstein, Cristina Fillat, Xavier Estivill, Victor L. J. Tybulewicz, Elizabeth M. Fisher, Stylianos E. Antonarakis & Dean Nizetic.
DYRK1A dosage imbalance perturbs NRSF/REST levels de-regulating pluripotency and embryonic stem cell fate in Down syndrome.American Journal of Human Genetics Volume 83, Issue 3, 388-400, 04 September (2008).
[ http://news.bbc.co.uk/1/hi/health/7597761.stm ]
• Jürgen Groet, Claire Mulligan, Monica Spinelli, Anna Serra, Suzanne McElwaine, Finbarr E. Cotter, Franca Dagna-Bricarelli, Giuseppe Saglio, Giuseppe Basso and Dean Nizetic . Independent clones at separable stages of differentiation, bearing different GATA1 mutations in the same TMD patient with Down Syndrome. Blood, 106(5):1887-1888 (2005).
• Aideen O Doherty, Sandra Ruf, Claire Mulligan, Victoria Hildreth, Mick L. Errington, Sam Cooke, Abdul Sesay, Sonie Modino, Lesley Vanes, Diana Hernandez, Jacqueline M. Linehan, Paul T. Sharpe, Sebastian Brandner, Timothy V.P. Bliss, Deborah J. Henderson, Dean Nizetic, Victor L.J. Tybulewicz, Elizabeth M.C. Fisher. An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes. Science , 309(5743):2033-2037, 23rd September (2005).
• Suzanne McElwaine, Claire Mulligan, Jürgen Groet, Monica Spinelli, Andrea Rinaldi, Gareth Denyer, Afua Mensah, Simona Cavani, Chiara Baldo, Franca Dagna-Bricarelli, Ian Hann, Giuseppe Basso, Finbarr E Cotter and Dean Nizetic . Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker. British Journal of Haematology , 125:729-742 (2004).
• Jürgen Groet, Suzanne McElwaine, Monica Spinelli, Andrea Rinaldi, Ingo Burtscher, Claire Mulligan, Afua Mensah, Simona Cavani, Franca Dagna-Bricarelli, Giuseppe Basso, Finbarr E Cotter and Dean Nizetic Acquired mutations in GATA1 in neonates with Down syndrome with Transient Myeloid Disorder. Lancet , 361:1617-1620 (2003).
• Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X, Bouman D, Li Y, Mehta, PK, Nizetic D, Kaneko Y, Chan GC, Chan LC, Squire J, Scherer SW, Hitzler JK. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genetics , Jul;28(3):220-221 (2001).
• M. Hattori, A. Fujiyama, T. D. Taylor, H. Watanabe, T. Yada, H.-S. Park, A. Toyoda, K. Ishii, Y. Totoki, D.-K. Choi, E. Soeda, M. Ohki, T. Takagi, Y. Sakaki, S. Taudien, K. Blechschmidt, A. Polley, U. Menzel, J. Delabar, K. Kumpf, R. Lehmann, D. Patterson, K.Reichwald, A. Rump, M. Schillhabel, A. Schudy, W. Zimmermann, A. Rosenthal, J. Kudoh, K. Shibuya, K. Kawasaki, S. Asakawa, A. Shintani, T. Sasaki, K. Nagamine, S. Mitsuyama, S. E. Antonarakis, S. Minoshima, N. Shimizu, G. Nordsiek, K. Hornischer, P. Brandt, M. Scharfe, O. Schön, A. Desario, J. Reichelt, G. Kauer, H. Blöcker, J. Ramser, A. Beck, S. Klages, S. Hennig, L. Riesselmann, E. Dagand, S. Wehrmeyer, K. Borzym, K. Gardiner, D. Nizetic , F. Francis, H. Lehrach, R. Reinhardt & M.-L. Yaspo. The DNA sequence of human chromosome 21. Nature 405, 311 - 319 (2000).
