Myelination and Repair in the CNS

Group leader: 
Charles ffrench-Constant
Professor of Medical Neurology; Director; Theme leader Neural Differentiation and Tissue Repair

cffc [at] ed [dot] ac [dot] uk

Alasdair Rooney (PhD Student)
Alexander Raven (PhD Student, co-supervised by Prof Stuart Forbes)
Andrew Jarjour (Post Doc)
Katie Long (Post Doc)
Matthew Swire (PhD Student)
Marie Bechler (Post Doc)
Marie Harrisingh (Post Doc)
Max Ahmed (Post Doc)
Roly Megaw (PhD Student)
Tim Czopka (Post Doc)
AimsThe principal focus of our research is multiple sclerosis (MS), an inflammatory progressive disease in which the myelin around the axons of the Central Nervous System (CNS) is damaged. We identify molecules and signalling pathways that can be used to enhance repair in the damaged CNS. Additionally, ongoing collaborative projects in our laboratory also address spinal-cord injury and schizophrenia.BackgroundThe 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.(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.We study CNS neural stem cells and oligodendrocytes. The logic is that the neural stem cells that generate neurons and glia throughout life provide a potential source of cells for CNS regeneration, while the oligodendrocytes that normally form myelin represent the cell type responsible for repair in MS. To identify the molecules and signaling pathways that regulate these cells, we focus principally on the interaction between integrin receptors and their extracellular matrix ligands of the laminin family - an interaction critical for many developmental processes and one for which, as the extracellular matrix changes profoundly in response to injury, a better understanding is essential if we are to promote repair.Approaches and progressTo examine the biology of neural stem cells we study the developing cortex in the brain, where the neural stem cells are dividing rapidly to generate neurons. We also study the adult subependymal zone where neural stem cells divide slowly unless the CNS is injured.In both cases, we have found that the microenvironment or niche of the stem cells is rich in extracellular matrix molecules of the laminin family. To test the role of these laminins we injected integrin-blocking antibodies directly into the ventricle of embryonic mice. These experiments showed that the integrins were required for retention of the dividing stem cells in their niche, and we are currently testing the effects of activating or inhibitory integrin mutants on stem cell divisions.Our previous work on oligodendrocytes showed how integrins regulate target dependent survival of these cells by amplifying growth factor signaling once axonal contact is established.More recently we have turned to the question of CNS myelination itself, a process that we still understand extremely poorly. Using transgenic mice we have shown that integrins contribute to the signals that initiate myelination. To understand the signaling mechanisms we have developed co-culture models where each step of myelination can be targeted. Using these we have shown how integrins complex with another cell adhesion molecule, contactin-1, to activate the necessary Src-family kinase signaling upon axonal contact. We have also shown how integrins regulate the translation from myelin basic protein mRNAs within each oligodendrocyte process, so providing a mechanism by which axoglial contact can be linked to the appropriate level of production of myelin proteins.In the event of an insult against the myelin sheath or the oligodendrocyte in general, the cell will undergo apoptosis. Inflammatory signals can then activate resident oligodendrocyte progenitor cells, which will proliferate and migrate to the affected region where they will then initiate remyelination.  Selected publicationsJarjour A, Zhang H, Bauer N, ffrench-Constant C and Williams A. 2012. In vitro modeling of central nervous system myelination and remyelination. Glia, 60:1–12. doi: 10.1002/glia.21231.Laursen LS, Chan CW, Ffrench-Constant C. 2011. Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K. The Journal of Cell Biology 92(5):797-811. doi: 10.1083/jcb.201007014.Huang JK, Jarjour AA, Oumesmar BN, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Baron-Van Evercooren A, Chambon P, ffrench-Constant C, Franklin RJM. 2010. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience 14(1):45-53. doi:10.1038/nn.2702 2. Press release.Câmara J, Wang Z, Nunes-Fonseca C, Friedman HC, Grove M, Sherman DL, Komiyama NH, Grant SG, Brophy PJ, Peterson A, ffrench-Constant C. 2009. Integrin-mediated axoglial interactions initiate myelination in the central nervous system. Journal of Cell Biology 185(4):699-712. doi: 10.1083/jcb.200807010.Loulier K, Lathia JD, Marthiens V, Relucio J, Mughal MR, Tang SC, Coksaygan T, Hall PE, Chigurupati S, Patton B, Colognato H, Rao MS, Mattson MP, Haydar TF, Ffrench-Constant C. 2009. Beta1 integrin maintains integrity of the embryonic neocortical stem cell niche. PLoS Biology 7(8):e1000176. doi:10.1371/journal.pbio.1000176.Laursen LS, Chan CW, ffrench-Constant C. An integrin-contactin complex regulates CNS myelination by differential Fyn phosphorylation. The Journal of Neuroscience 29(29):9174-85. doi: 10.1523/JNEUROSCI.5942-08.2009.Franklin RJ, Ffrench-Constant C. 2008. Remyelination in the CNS: from biology to therapy. Nature Reviews Neuroscience 9(11):839-55. doi:10.1038/nrn2480.CollaborationsWe have an extensive network of collaborations.Within MRC-CRM and the Edinburgh Centre for Neuroregeneration (CNR), we work closely with Dr David Lyons, Dr Sally Lowell and Dr Anna Williams to apply the advantages of zebrafish, ES cells and explant cultures to our work on oligodendrocytes.With Prof Robin Franklin (University of Cambridge) we examine the effect of manipulating oligodendrocyte signaling pathways on remyelination, and also the role of inflammation in promoting regeneration.With Prof James Fawcett (University of Cambridge) we are exploring whether expressing integrins that bind to tenascins in the extracellular matrix scar that follows spinal cord injury will promote regeneration.With Prof Andreas Faissner (Ruhr-Universität Bochum) we are defining the roles of tenascins in CNS development.With Prof David Porteus (Centre for Integrative Physiology at the University of Edinburgh) we are examining stem cell behaviour in the CNS of mouse models of psychiatric disease.FundingMedical Research CouncilMultiple Sclerosis SocietyWellcome TrustEuropean Leucodystrophy Association Image credits figure 1 and 2© All Rights Reserved Dr Nina Bauer.