One of the reasons that repair fails after injury to the central nervous system (CNS) is that many CNS neurons respond weakly and make little attempt to re-grow their axons. This contrasts with axotomised neurons after peripheral nerve injury, which do regenerate vigorously, upregulating many genes in what is known as the regeneration-associated gene (RAG) program. My research is focused on understanding the neuronal gene expression controlling axonal regeneration, and how this can be manipulated to promote axon regeneration. This approach involves several strands of research.
Overexpression of transcription factors
In this line, the goal is to induce the activation of the neuronal regeneration-associated gene (RAG) program in PNS and CNS neurons by delivering combinations of transcription factors. The aim here is effectively to re-program neurons into a regenerative state. Currently we are doing this in dorsal root ganglion neurons to promote regeneration after lesion of the central axon branches of these neurons. This model is comparable to the conditioning lesion paradigm, whereby a peripheral nerve lesion activates the RAG program in these sensory neurons and promotes central sprouting/regeneration.
Analysis of gene expression
Key to the approach is identifying which transcription factors are needed for RAG expression. We use genome wide gene expression profiling to understand the regulatory network controlling RAG expression. For example, we have been studying the effect of deletion of c-Jun, a transcription factor linked to successful axon regeneration, on RAG expression. This approach has given several insights into the RAG program, not only identifying target genes and functional effects of c-Jun, but also giving a high-quality dataset which allowed the development and testing of bioinformatics tools for promoter analysis. In order to gain insight into what are the key transcription factors controlling RAG expression, I analyse the promoters of differentially expressed genes to identify over-represented binding sites. This is done using multiple cross-species conservation to consider only evolutionarily conserved sites. Using this approach has allowed us to identify key transcription factors involved in the RAG program, some of which are novel.
I am interested in the use of viral vectors to deliver therapeutic gene expression to injured neurons in vivo. Adeno-associated viral vectors are currently the optimal vector for this purpose, and with these vectors we are able to transduce DRG neurons with very high efficiency. These vectors also target other spinal projection neurons with high efficacy (e.g. rubrospinal tract, corticospinal tract). One of my research interests is to further develop these tools for in vivo regeneration experiments. For example, we developed a dual gene expression vector which allows robust expression of a gene of interest and GFP, allowing specific visualization of transduced neuronal fibres.
Further interests include statistics, bioinformatics, data analysis, programming (R, Scala) and image analysis.
Matthew Mason studied Natural Sciences at Cambridge University, with specialization Genetics. He followed this with an MSc in Neuroscience at University College London (UCL) and obtained his PhD in the field of neuroregeneration under Prof. Patrick Anderson at UCL. After post-doctoral work at UCL he came to the Verhaagen lab.
- Andrews MR, Soleman S, Cheah M, Tumbarello DA, Mason MR, Moloney E, Verhaagen J, Bensadoun JC, Schneider B, Aebischer P, Fawcett JW. (2016) Axonal Localization ofIntegrins in the CNS Is Neuronal Type and Age Dependent. eNeuro. 2016 3(4). pii: ENEURO.0029-16.2016. doi: 10.1523/ENEURO.0029-16.2016.
- Fagoe ND, Attwell CL, Eggers R, Tuinenbreijer L, Kouwenhoven D, Verhaagen J,Mason MR. (2016) Evaluation of Five Tests for Sensitivity to Functional Deficitsfollowing Cervical or Thoracic Dorsal Column Transection in the Rat. PLoS One.2016 11(3):e0150141. doi: 10.1371/journal.pone.0150141.
- Fagoe ND, Attwell CL, Kouwenhoven D, Verhaagen J, Mason MR. (2015) Overexpression of ATF3 or the combination of ATF3, c-Jun, STAT3 and Smad1 promotes regeneration of the central axon branch of sensory neurons but without synergistic effects. Hum Mol Genet 2015 24:6788-800.
- Fagoe N.D., Eggers R., Verhaagen J., Mason M.R.J. (2015) Gene Delivery to Neurons of the Dorsal Root Ganglia Using Adeno-Associated Viral Vectors. Gene Delivery and Therapy for Neurological Disorders (Bo X, Verhaagen J, eds), New York: Humana Press.
- Fagoe N.D., Eggers R., Verhaagen J., Mason M.R. (2014) A compact dual promoter adeno-associated viral vector for efficient delivery of two genes to dorsal root ganglion neurons. Gene Ther 21:242-252.
- de Winter F., Hoyng S., Tannemaat M., Eggers R., Mason M., Malessy M., Verhaagen J. (2013) Gene therapy approaches to enhance regeneration of the injured peripheral nerve. Eur J Pharmacol 719:145-152.
- Verhaagen J., Van Kesteren R.E., Bossers K.A., Macgillavry H.D., Mason M.R., Smit A.B. (2012) Molecular target discovery for neural repair in the functional genomics era. Handb Clin Neurol 109:595-616.
- Mason M.R., Tannemaat M.R., Malessy M.J., Verhaagen J. (2011) Gene therapy for the peripheral nervous system: a strategy to repair the injured nerve? Curr Gene Ther 11:75-89.
- Van Kesteren R.E., Mason M.R., Macgillavry H.D., Smit A.B., Verhaagen J. (2011) A gene network perspective on axonal regeneration. Front Mol Neurosci 4:46.
- Mason M.R., Ehlert E.M., Eggers R., Pool C.W., Hermening S., Huseinovic A., Timmermans E., Blits B., Verhaagen J. (2010) Comparison of AAV serotypes for gene delivery to dorsal root ganglion neurons. Mol Ther 18:715-724.
- Stam F.J., Mason M.R., Smit A.B., Verhaagen J. (2008) A Meta-Analysis of Large-Scale Gene Expression Studies of the Injured PNS: Toward the Genetic Networks That Govern Successful Regeneration. Neural Degeneration and Repair: Gene Expression Profiling, Proteomics and Systems Biology. (Müller HW, ed), pp 35-60. Hoboken, N.J.: Wiley.
- Groutsi F., Mason M.R., Anderson P.N., Martins S., Anesti M., Coffin R.S., Campbell G. (2008) Retrograde viral transduction of cortical pyramidal neurons from the spinal cord. Restor Neurol Neurosci 26:509-520.
- Tannemaat M.R., Korecka J., Ehlert E.M., Mason M.R., van Duinen S.G., Boer G.J., Malessy M.J., Verhaagen J. (2007) Human neuroma contains increased levels of semaphorin 3A, which surrounds nerve fibers and reduces neurite extension in vitro. J Neurosci 27:14260-14264.
- Hossain-Ibrahim M.K., Rezajooi K., MacNally J.K., Mason M.R., Lieberman A.R., Anderson P.N. (2006) Effects of lipopolysaccharide-induced inflammation on expression of growth-associated genes by corticospinal neurons. BMC Neurosci 7:8.
- Hunt D., Hossain-Ibrahim K., Mason M.R., Coffin R.S., Lieberman A.R., Winterbottom J., Anderson P.N. (2004) ATF3 upregulation in glia during Wallerian degeneration: differential expression in peripheral nerves and CNS white matter. BMC Neurosci 5:9.
- Mason M.R., Lieberman A.R., Anderson P.N. (2003a) Corticospinal neurons up-regulate a range of growth-associated genes following intracortical, but not spinal, axotomy. Eur J Neurosci 18:789-802.
- Mason M.R., Lieberman A.R., Latchman D.S., Anderson P.N. (2003b) FKBP12 mRNA expression is upregulated by intrinsic CNS neurons regenerating axons into peripheral nerve grafts in the brain. Exp Neurol 181:181-189.
- Mason M.R., Lieberman A.R., Grenningloh G., Anderson P.N. (2002) Transcriptional upregulation of SCG10 and CAP-23 is correlated with regeneration of the axons of peripheral and central neurons in vivo. Mol Cell Neurosci 20:595-615.
- Hunt D., Mason M.R., Campbell G., Coffin R., Anderson P.N. (2002) Nogo receptor mRNA expression in intact and regenerating CNS neurons. Mol Cell Neurosci 20:537-552.
- Mason M.R., Campbell G., Caroni P., Anderson P.N., Lieberman A.R. (2000) Overexpression of GAP-43 in thalamic projection neurons of transgenic mice does not enable them to regenerate axons through peripheral nerve grafts. Exp Neurol 165:143-152.
- Harding D.I., Greensmith L., Mason M., Anderson P.N., Vrbova G. (1999) Overexpression of GAP-43 induces prolonged sprouting and causes death of adult motoneurons. Eur J Neurosci 11:2237-2242.