Dr Vincent T Cunliffe

Henry

Vincent Cunliffe graduated from the University of Edinburgh in 1986 with First Class Honours in Molecular Biology. In 1990 he was awarded a PhD in Zoology from University College London, for molecular biological studies of the mammalian zinc finger gene superfamily, which were carried out at the Imperial Cancer Research Fund Laboratories under the supervision of John Trowsdale.After a post-doctoral post in Seattle with Richard Palmiter, Vincent carried out further post-doctoral work with Jim Smith at NIMR, London, investigating the transcriptional regulation and developmental function of the Brachyury transcription factor in Xenopus. In 1994 Vincent was appointed to the post of Group Leader in Molecular and Cell Biology at the UK Biotechnology company Therexsys Limited. In 1997 he was awarded a Lister Institute Research Fellowship to pursue independent research on the control of chromatin activity during vertebrate development, in the Centre for Developmental Genetics at the University of Sheffield. Vincent was appointed to a Lectureship in the Department of Biomedical Science in 2002 and promoted to Senior Lecturer in 2007.

Research

Summary for nonspecialist

During development of the embryonic nervous system, undifferentiated, actively dividing neural stem cells are transformed into functional nerve and other brain cell types by poorly understood molecular mechanisms. If we could understand how neural stem cell behaviour is governed, then it may be possible to use this knowledge to develop new treatments for nervous system diseases and to repair damage caused by accidental injury. The zebrafish is an ideal organism for experimental investigations into the mechanisms controlling the transformation of stem cells into nerve cells, because of the transparency of the embryo, which allows direct observation of cellular processes occurring deep within the developing brain, and because of the many mutations known to disrupt development of the zebrafish nervous system in a variety of important ways.

The molecular processes that govern the balance between the transformation of neural stem cell into nerve cells, production of more stem cells, or a mixture of both, include a system that regulates a cell's access to the information contained within the genes in its nucleus. Distinct cell types exhibit different repertoires of active genes, and once specified, these differences are maintained over long periods of time, which sometimes extend from embryogenesis into adult life. The molecular mechanisms underlying such long-term decisions act at the level of gene transcription, which is the first step in a cell's decoding of the information that resides within its gene sequences, and used to construct proteins and other molecules that do the work of the cell and give it a characteristic set of physiological capabilities. My laboratory is interested in understanding how this decoding mechanism functions in cell decision-making and thus confers long-term memory of cellular identity to individual cells during development. We are also very interested in understanding how this decoding mechanism can be rendered dysfunctional in human diseases such as cancer.

A second area of interest stems from the relative ease with which the zebrafish embryo can be used to investigate complex biological processes and the amazing extent to which the vast majority of human genes have near-exact counterparts in the zebrafish. We are therefore taking advantage of these features of the zebrafish to investigate the biological functions of genes whose human counterparts, when damaged or inactivated, play pivotal roles in neurological disorders. One such gene of interest is SPASTIN, alteration of which is a frequent cause of the motorneurone disease Hereditary Spastic Paraplegia. We have shown that in zebrafish, Spastin is involved in promoting the growth of nerve processes in the embryo which contact body muscles and regulate muscle contraction, which provides strong experimental support for the idea that in humans, defects in the Spastin gene likely impair nerve outgrowth or maintenance. Future studies will investigate how the Spastin protein fits into the mechanism driving the growth of nerve processes. Another ongoing project has adopted an approach similar to that taken for Spastin, to understand the functions of two genes known to be involved in schizophrenia, and we have obtained some new leads on the likely roles of these genes in human brain development by studying the functions of their zebrafish counterparts.

A third area of interest is in developing tools for growing and studying laboratory cultures of human stem cells, and is based on an ongoing programme of collaborative research with an academic engineering group and an industrial partner to develop novel cell culture materials that are capable of supporting the expansion and directed differentiation of isolated stem cells.

Figure 1

Technical Summary

Our research is focused primarily on understanding the roles of chromatin regulatory proteins in the development of the zebrafish Central Nervous System (CNS), and where appropriate, investigating the relevance of these findings for understanding human disease mechanisms. In addition, we have been exploiting the technical advantages of the zebrafish embryo for in vivo analysis of gene functions, to investigate the molecular and cellular functions of genes previously implicated in human neurological disease processes. Current projects include:

1. Elucidation of the roles of class I Histone deacetylases in zebrafish CNS development.

HDACs are critical components of the transcription silencing machinery and enzymatically antagonise the transcriptional activiation functions of Histone Acetyltransferases. Much of our recent work has focused on elucidating the function of Histone Deacetylase 1 (Hdac1) in specification of multiple neural fates in the embryonic brain and spinal cord, and we are utilising global gene expression profililng tools to characterise Hdac1-regulated developmental pathways in the developing CNS. We have recently extended this work to include an analysis of the role of Hdac3 in neural development, and are also investigating the utility of small molecule HDAC inhibitors as tools for the conditional inhibition of class I HDAC function during embryogenesis.

2. Investigation of the functions of Polycomb genes in development and disease.

Polycomb Group proteins are key components of several distinct multisubunit transcriptional repression complexes that are implicated in many developmental and disease processes. We have begun to elucidate the functions of Polycomb Group proteins in zebrafish CNS development, and in collaboration with Dr Richard Bryant and Professor Freddie Hamdy (Academic Urology Unit, University of Sheffield School of Medicine) we have recently made progress towards understanding the functions of the Polycomb Group gene EZH2, which encodes a histone methyltransferase transcriptional repressor, in progression of prostate cancer.

3. Investigation of the developmental functions of zebrafish orthologues of human neurological disease genes

The technical advantages of the zebrafish system for gene function analysis include (a) genetic tractability, (b) optical clarity of the embryo, (c) robust tolerance to microinjection with antisense oligonucleotides, synthetic mRNA or plasmid DNA, (d) amenability to cell transplantation to create genetic mosaics, and (e) the extensive genetic similarity between the human and zebrafish genomes. These manifold qualities make the zebrafish an excellent model vertebrate system in which to investigate the functions of genes whose dysfunction or dysregulation are important factors in human disease mechanisms. In collaboration with Dr Jonathan Wood and Professor Pamela Shaw (Academic Neurology Unit, University of Sheffield School of Medicine) and Professor Christopher Ross (Johns Hopkins University, Baltimore, USA) our current studies are focused on understanding how human genes contribute to the aetiology of Hereditary Spastic Paraplegia and Schizophrenia, by elucidating the roles of corresponding zebrafish orthologues in early development of the CNS. This experimental work combines live imaging of neuronal development and axon outgrowth with genetic and pharmacological manipulation of gene and protein functions, in order to reveal how dysfunction of specific genes may perturb normal cell behaviours in the CNS.

4. In vitro systems for ex vivo manipulation of stem cells.

In collaboration with BD Biosciences and Professor Robert Short at University of South Australia, Adelaide, we have precision-engineered novel tissue culture surfaces that are able to control the differentiation capacity of in vitro cultured adherent cells. These surfaces have been engineered to contain either homogeneous fields or sub-millimetre-scale gradients of intercellular signalling proteins, which can be tethered to the surface either covalently or non-covalently.

Contact details

Dr Vincent Cunliffe

MRC Centre for Developmental and Biomedical Genetics
The University of Sheffield
Firth Court, Western Bank
Sheffield S10 2TN
United Kingdom


Room: D18 Firth Court
Office: +44 (0) 114 222 2389
Lab: +44 (0) 114 222 2381
Fax: +44 (0) 114 276 5413

email: v.t.cunliffe@sheffield.ac.uk

PhD Opportunity

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