Myelination and repair in the CNS

The CNS consists of the brain and the spinal cord and is made up of nerve cells (neurons) and glial cells. The neurons transmit information from one cell to another, while the glial cells support and protect the neurons. Oligodendrocytes, one of the supporting glial cell types, form the myelin that insulates the axons of neurons (figure). These cells are damaged in MS, and can be replaced by new oligodendrocytes formed by stem cell-like oligodendrocyte precursors. In MS this repair fails, and overcoming this failure is the focus of our research with specific goals being i) the mechanisms by which oligodendrocytes form a myelin sheath and ii) how the stem cells in the CNS become activated to contribute to oligodendrocyte replacement.

(A) Oligodendrocytes in culture develop from an oligodendrocyte progenitor cell by extending processes and ultimately forming sheet-like myelin protein-containing protrusions. (B) In the presence of neurites, oligodendrocyte progenitor cells extend their processes, and upon contact formation with a neurite initiate a wrapping process, which will subsequently form the compact myelin sheath.

To address these goals I have explored the overlap between developmental and regenerative biology ever since, as a graduate student in Martin Raff’s lab, I described for the first time the proliferating glial progenitor cell in the adult CNS (Nature 1986). This cell is now recognised as one of the adult stem cell populations of the CNS. My postdoctoral work with Richard Hynes at MIT continued this theme, showing how re-expression of embryonic patterns of alternative splicing of fibronectin provided a mechanism for promoting repair in skin wound healing (J Cell Biol 1989).

Since starting my own laboratory in Cambridge in 1991 (whence I moved to Edinburgh in 2007) my work has explored three areas of developmental and regenerative biology: first, the mechanisms that regulate myelination; second, neural stem cell renewal and differentiation; and, third, the extent to which successful regeneration recapitulates development.

The theme that initially underpinned all these projects was extracellular matrix and its integrin receptors. In oligodendrocyte biology, my lab has shown that integrins provide a novel mechanism for target-dependent survival, a key process in CNS development (Curr Biol 1999, Nat Cell Biol 2002). Signalling in response to the very low concentrations of growth factors present in vivo is amplified by integrins co-located with growth factor in lipid raft microdomains (EMBO J 2002, Curr Biol 2003, J Neurosci 2004) and, as the axon provides the ECM ligand (laminin) for these integrins, this ensures that only contacting oligodendrocytes survive. We went to show the signalling pathways involved, with integration of signals by the Src-family kinase Fyn (J Cell Biol 2004) and the involvement of multiple laminin receptors (Development 2007).

Over the last 5 years we have, funded by a Wellcome Trust programme grant, set out to test the hypothesis that the mechanisms responsible for target-dependent survival of oligodendrocytes are also responsible for regulating myelination itself. We confirmed this hypothesis (J Cell Biol 2009), and used proteomics of integrin-associated signaling molecules to identify an integrin-contactin complex that activates Fyn to promote myelination (J Neurosci 2009). In further studies, we then showed that this complex regulated the local translation of myelin basic protein mRNAs via an interaction with hnRNPK (J Cell Biol 2011), so providing a mechanism for the remarkable ability of the oligodendrocyte to generate multiple myelin sheaths each of a size appropriate for the axon it ensheaths. We will now, funded by a Wellcome Trust Senior Investigator Award, continue this by identifying other mechanisms for myelin sheath formation such as polarity signalling, and establishing the relative contributions of intrinsic and extrinsic signalling pathways to this most spectacular cell-cell interaction.

Building on these developmental studies of myelination, we have also developed three related research strands. First, we have (in collaboration with Robin Franklin, Cambridge) examined remyelination, with the goal being to initiate drug discovery programmes for the progressive MS that results from failed remyelination. We have discovered three new targets by analyzing the glial and microglial response to injury in animal models – RXRgamma (Nat Neurosci 2011), endothelin receptor B (Brain 2013) and activin-A (Nat Neurosci 2013). The RXRgamma and activin-A projects are currently being continued with translational funding streams (the latter by the post doc who performed the work and is now an independent PI), and our approach is outlined in a very highly cited review (Nat Rev Neurosci 2008). Second, we have used the technologies we developed in our studies of myelination to examine integrin function in neural stem cells. We find upregulation on stem cell activation (J Neurosci 2010) and a requirement for integrins in apical process attachment to ventricular surface (PLoS Biol 2009) – leading to the hypothesis that maintaining shape is critical for stem cell function (EMBO Rep 2009, J Cell Sci 2010). This work on integrins and their ECM ligands is being continued in work funded by an FP7 project NeurostemcellRepair and by an NIH-funded collaboration with colleagues in the US. Third, we have developed our work on integrins in nerve regeneration showing how chimeric integrins can be used to convert neutral or inhibitory substrates into those that promote axon growth (J Neurosci 2001, J Neurosci 2009), a strategy currently being tested in the CNS in collaboration with James Fawcett, Cambridge and funded by an MRC programme grant.

Related activities

Prof Charles ffrench-Constant is also Director of Edinburgh Neuroscience (2013 – onwards), Co-Director of the Anne Rowling Regenerative Neurology Clinic (2012 – onwards), and Director of the University of Edinburgh/Multiple Sclerosis Research Centre (2007 – onwards).

• Edinburgh Neuroscience is a Centre without walls, hosted by the University of Edinburgh’s College of Medicine and Veterinary Medicine and currently consists of approximately 400 staff, 140 postdoctoral researchers, 230 PhD students and 30 MSc students, working in approximately 120 research laboratories. It aims to integrate basic and clinical research in order to drive the fundamental genetic, cellular, organ, systems and computational neuroscience underpinning pathogenesis into mechanistic understanding, future diagnostics and therapeutics of important diseases of the nervous system.
• The Anne Rowling Regenerative Neurology Clinic is a clinical research facility that focuses on a wide range of neurological conditions, especially neurodegenerative diseases. Work in the Clinic is closely linked to CRM with the ffrench-Constant, Chandran, Kaji, Kunath and Williams research groups all examining the underpinning biology of these diseases and the technologies required to study them.
• The University of Edinburgh/Multiple Sclerosis Research Centre is part of the MRC Centre for Regenerative Medicine. It was set up in 2007 supported by at £2M grant from the MS Society with generous support from the Volant Trust as a research centre dedicated to studying Multiple Sclerosis (MS). Researchers aim to: 1) build on early laboratory discoveries to understand how myelin repair fails in people with MS, 2) work closely with the MS Society Cambridge Centre for Myelin Repair towards clinical trials for myelin repair therapies for people with MS, and 3) continue early stage research to develop potential therapies for people with progressive forms of MS.