All Seminars are held in the Gavin De Beer Lecture Theatre, Anatomy Building, Thursday 1-2pm
26 March: Lizzie Yates (Patel lab) / Melissa Barber (Parnavelas lab)
9 April: Zeki lab –TBC/ Francis Carpenter (Caswell Barry lab)
23 April: Florent Peglion (Nate Guring lab)/Michele Sammut (Barrios lab, now in Poole lab)
Professor Patrick Anderson
Patrick Anderson is Professor of Experimental Neuroscience
View Prof Anderson's Lab Pages
Regeneration in the injured mammalian brain and spinal cord
Brain or spinal cord injuries have devastating consequences and cannot yet be repaired. Much of their effect is the result of damage to axons which, unlike their counterparts in peripheral nerves, do not normally regenerate. Unfortunately, although there have been several exciting reports of axonal regeneration in the mammalian spinal cord in recent years, few if any of these apparent breakthroughs have been replicated in different laboratories, and there is still no consensus as to the reasons for the failure of axonal regeneration in the CNS. The aims of our laboratory are to gain an understanding about what normally prevents axonal regeneration in the CNS, and to use this knowledge to develop strategies for improving the repair of CNS lesions such as spinal injuries and stroke.
The expertise in our lab is in experimental surgery, neuroanatomy, electron microscopy, immunohistochemistry, in situ hybridisation and molecular biology. These techniques are essential for careful and accurate investigation of axonal regeneration. With our collaborators in the UK, Holland, Germany and the USA we generate and investigate transgenic mice to identify molecules that are important for axonal regeneration, and use viral vectors for gene therapy experiments to promote regeneration. Overall we seek to gain greater knowledge of the events occurring in the damaged nervous system, while trialing promising approaches to enhancing axonal regeneration.
Ideas behind our research include:
(i) Identifying neuronal genes that control regeneration. The ability of neurons to regenerate axons is determined by their ability to express growth-related genes after injury. Regenerative capacity is correlated with expression of transcription factors such as c-jun and ATF3, growth cone proteins such as GAP-43, CAP-23 and SCG10, and the adhesion molecules L1 and CHL1. Increasing the expression of these genes by injured CNS neurons may be an essential element in repairing the injured brain and spinal cord.
(ii) Identifying inhibitory molecules and their receptors in the injured nervous system. The dominant hypothesis seeking to explain the absence of regeneration in the CNS is that axonal elongation is normally prevented by inhibitory molecules. Many molecules that are capable of blocking neurite elongation in vitro are present in CNS tissue. These include NG2, Nogo and extracellular matrix molecules. We want to establish if any of these are really important in preventing regeneration.
(iii) Prevention of secondary damage. Much of the damage to axons following spinal injury occurs after the initial lesion. This provides a window of opportunity for reducing the effects of injury. This work has immediate clinical relevance and is a developing part of our research programme.
Techniques used and recent results
Transgenic animals can be used to demonstrate the importance of
individual molecules for the regeneration of CNS
Overexpressing individual growth-associated molecules, such as GAP-43 and L1, has limited effects on axonal regeneration in the CNS, probably because a whole program of genes must be expressed to regenerate axons vigorously. Transcription factors, which can control the expression of other genes, are now our favoured targets. Knocking out growth-related molecules should enable their importance to be established. Sometimes conventional knockouts are not suitable for regeneration experiments because of their role in development and we are currently generating conditional knockouts for several molecules including GAP-43, SCG10 and CAP-23. ATF3 knockouts are being investigated; if ATF3 is an important switch controlling axonal regeneration, recovery from nerve injury to the mutants should be poor. Knocking out inhibitory molecules should dramatically improve axonal regeneration if such molecules form a significant barrier for regenerating axons. We have tested regeneration in the spinal cord in tenascin-R knockouts and NG2 knockouts, and our results suggest that neither molecule is responsible for preventing axonal regeneration in the spinal cord.
distribution of growth-inhibitory molecules and their
We recently showed that the Nogo-66 receptor (NgR) was only expressed by a minority of neurons and could not explain the general failure of regeneration in the CNS. We are now investigating genes closely related to NgR. Similarly we have shown that NG2, widely believed to be a major inhibitory protein in the damaged spinal cord, is also strongly expressed in injured peripheral nerves where regeneration is vigorous. Gene therapy. In collaboration with Rob Coffin at UCL and J. Verhaagen in Amsterdam we are exploring gene therapy approaches to improving the outcome of spinal cord injury. We have shown that when spinal cord neurons and glia are transfected with the NT-3 gene using an adenovirus vector, regenerating dorsal root axons enter the cord in large numbers and regenerate deep into the grey matter. Unfortunately, delivery of neurotrophins to the CNS is less effective at producing regeneration of axons in ascending and descending tracts within the spinal cord, probably because of inhibitory molecules at lesion sites. We are now developing vectors that can deliver to neurons enzymes that can digest inhibitory molecules (metalloproteases), or deliver antisense (siRNA) sequences to block the expression of receptors for inhibitory molecules. A related approach is the use of conventional antisense oligonucleotides, which we have shown can readily penetrate the spinal cord and knock down gene expression. Increasing axonal sprouting and regeneration by other methods. We are testing various unconventional approaches to produce greater regeneration in the spinal cord. Vaccination with extracts of CNS tissue (myelin, lesion scars) induces the production of antibodies against inhibitory molecules. In our hands this enhances axonal sprouting in the injured spinal cord, but does not lead to long-distance regeneration. Inflammation around neuronal cell bodies has also been shown to increase expression of growth-associated molecules and enhance sprouting of corticospinal axons in the spinal cord. Reducing secondary injury. We have shown that treatment with the immunosuppressant FK506 or antisense connexin 43 are neuroprotective and improve recovery from spinal cord injury.
Ph.D Southampton - 1974
Pasterkamp, R.J., Anderson, P.N. and Verhaagen, J. (2001) Peripheral nerve injury fails to induce growth of lesioned ascending dorsal column axons into spinal cord scar tissue expressing the axon repellent Semaphorin 3A. European J. Neuroscience 13, 1-16.
Zhang, Y., Tohyama ,K., Winterbottom, J.K., Haque, N.S.K., Schachner, M., Lieberman, A.R. and Anderson, P.N. (2001) Correlation between putative inhibitory molecules at the dorsal root entry zone and failure of dorsal root axonal regeneration. Molecular & Cellular Neuroscience 17, 444-459.
Mason, M.R.J., Grenningloh G, Lieberman, A.R. Anderson, P.N.(2002) Transcriptional upregulation of SCG 10 and CAP-23 is correlated with the regeneration of the axons of peripheral and central Neurons in vivo. Molecular & Cellular Neuroscience 20, 595 615.
Hunt, D., Mason, M.R.J., Campbell, G., Coffin, R. and P.N. Anderson (2002) Nogo receptor mRNA expression in intact and regenerating CNS neurons. Molecular & Cellular Neuroscience 20, 537-552.
Hunt, D., Coffin, R.S. and Anderson, P.N. (2003) The Nogo receptor, its ligands and axonal regeneration in the spinal cord; A review. J. Neurocytology 31, 93-120. Hunt, D., Coffin, R., Prinjha,R.K. , Campbell, G. and Anderson, P.N. (2003) Nogo-A expression in the intact and injured nervous system. Molecular & Cellular Neuroscience 24, 1083-102.
Page last modified on 21 may 10 10:20 by Glenda Young