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- Reader in Developmental Neurobiology
- ICH Development Bio & Cancer Prog
- Institute of Child Health
- Faculty of Pop Health Sciences
The focus of my group has been on understanding how phosphotyrosine signalling regulates axonogenesis, neurogenesis and cancer in the nervous system, with particular interest in understanding the roles of the tyrosine-specific phosphatases (PTPs).
PTPs are highly expressed in developing neural tissues. I was the first to demonstrate that PTPsigma was enriched in spinal, sensory and retinal axons and that RPTPs were localised in growth cones. In the retinotectal system, we were the first to discover that RPTPs control the growth and targeting of axons in the avian retinotectal projection. We also showed that in a nerve regeneration system in vivo, RPTP gene expression responds rapidly to nerve crush lesions, suggesting that PTPs could play a part in nerve regeneration. Recent work by others on mice subsequently supported this hypothesis.
More recently we have been investigating the roles of the receptor-like PTPgamma and PTPsigma in spinal motor neuron development. Using short hairpin RNA vectors in ovo to suppress PTP expression, we have uncovered a novel role for these enzymes in controlling the generation and survival of motor neurons from spinal progenitors. These PTPs also control the lateral migration of neural precursors in the cord and could play a role in beta-catenin signalling.
As well as using developmental models, we generated insights into the molecular regulation of neural receptor PTPs (RPTPs). We documented the first ligand for PTPsigma in the embryonic nervous system, identifying heparan sulphate proteoglycans (HSPGs) as a novel class of high affinity binding partners. We are currently working towards understanding how HSPGS interact with PTPsigma at a structural level (collaboration with Dr Radu Aricescu, Oxford). My interest in the molecular regulation of RPTPs also led us to show that RPTP dimerisation is essential for ligand binding and furthermore that the differential ligand-binding properties of different PTPsigma isoforms is imposed through their rotational conformations. This knowledge is helping us to understand how the transduction of RPTP signals into cells is controlled.
We have shown that PTPsigma interacts directly with neurotrophin receptors (the Trk family) and can control NGF-dependent axon growth. A recently completed PhD project has also defined the complex co-expression patterns of RPTPs with Trk receptors in primary DRG neurons and has shown through shRNA knockdown of RPTP expression that these enzymes modulate Trk signalling.
Most recently, the laboratory has also begun to focus on neural cancer biology. There is increasing interest in PTPs as both tumour suppressors and oncogenes in cancers and we have evidence for both of these occurring in cancer of the nervous system. We have very recently started investigating the signalling pathways of PTPdelta in glioblastoma cells, with a focus in paediatric forms of the disease. We are also investigating the potential oncogenic role of PTPs as a class in neuroblastoma, a sympathoadrenal tumour of children. We have shown that vanadium metal derivatives are effective at inducing differentiation or death in a range of tumour-derived cell lines, synergising with retinoic acid (a well describe differentiation-inducing agent). We are now focussing on understanding the molecular basis of these findings, with the ultimate goal of providing new therapeutic opportunities in this disease. This cancer research fits well with our studies of Trk signalling since these kinases are also implicated in neuroblastoma aetiology. Our studies of RPTP regulation will also provide important insight into ways to potentially manipulation these enzymes for improved cancer treatment.
Our research in the RPTP field has produced many new insights and has placed us in a leading position in the UK. We have also acted as lead coordinator group for two EU Training Networks (FP5 in 2000 and FP6 in 2006)
My direct teaching roles are several-fold
1) Lecturing on cell signalling to MRes students at ICH
2) Direct research training of PhD students in my laboratory
3) Direct research training of MRes students at ICH
4) Skills training and career development of PhD students in an FP6 Research Training Network (PTPNET; I am the coordinator of this network). I also coordinated a related FP5 training network.
5) Teaching theory and practise of the chick embryo as a developmental model system. This is carried out annually at the Pasteur Institute on their Development and "Plasticity of the Nervous System" workshop programme.
6) Extended tutorial on the tyrosine phosphatase enzyme family, for MRC programme funded PhD students at the UCL LMCB.
I also have a central role at the Institute Child Health as Graduate Tutor for research students. The Institute has around 150 students and my role is to provide general support, advice, annual monitoring and several workshops for these students. I also carry out shortlisting and interviews for our annual student intake, and sit on PhD interviews and upgrade panels throughout the year.
|01-APR-2012||Departmental Graduate Tutor (Research)||Institute of Child Health||UCL, United Kingdom|
|01-OCT-2002||Reader||Institute of Child Health||UCL, United Kingdom|
|1986||PhD||Doctor of Philosophy – Genetics and Biochemistry||University College London|
|1985||MA||Master of Arts||University of Cambridge|
|1982||BA||Bachelor of Arts – Natural Sciences||University of Cambridge|