Jul 13, 2009
Team Funded by National MS Society’s Promise: 2010 Campaign Identifies Key Signals in Myelin Repair
A team funded in part by the National MS Society’s Promise: 2010 Campaign has demonstrated that the “Wnt signaling pathway” – a complex network of proteins that interact during brain development – may also play an important role in the failure of nerve-protecting myelin to repair itself in people with MS. Stephen P. J. Fancy, PhD, David Rowitch, MD, PhD (University of California, San Francisco) and colleagues – including Robin J. M. Franklin, PhD, DVM (University of Cambridge) report their findings in Genes and Development (2009 Jul 1;23(13):1571-85).
Drs. Rowitch and Franklin are members of the international Promise: 2010 Nervous System Repair & Protection team led by Professor Charles ffrench-Constant (University of Edinburgh and University of Cambridge, UK), who, along with three other collaborating teams, are laying the groundwork for clinical trials aimed at protecting and restoring function in people with MS.
Background: The symptoms of MS are caused by faulty nerve signals that are the result of damage to myelin, the material that insulates and protects nerve fibers, and to the nerve fibers themselves. In the brain and spinal cord, myelin is made and maintained by cells known as oligodendrocytes, which are also damaged in MS. Oligodendrocytes develop from precursor “stem” cells; for unknown reasons, these cells often fail to maintain their capacity for myelin repair in people with MS. One goal of MS research is to find ways to stimulate these precursors to make new oligodendrocytes that will repair the damaged myelin.
The Study: Dr. Rowitch’s team conducted high-tech screens to detect the activity of genes, called transcription factors, that control other genes. They screened for 1,040 transcription factor genes within the nervous systems of mice that were at key stages of recovery from myelin damage, trying to detect which genes were active during stages of myelin repair. The screen pointed to over 50 genes, of which the gene for a factor called “Tcf4” stood out, because it was most active in damaged areas where repair attempts were under way. Tcf4 is involved in the Wnt signaling pathway.
Up to now the Wnt pathway was known to be important in the early development of the brain and other tissues, but was not previously linked to myelin repair. The group followed up this effort with an elaborate series of experiments to further understand how Wnt signals might affect myelin repair. Among their findings, they demonstrated that causing the Wnt signals to be overly active in mice delayed myelin repair significantly. The team also examined tissue samples from people with MS, and found that Tcf4 was active only in areas damaged by MS, not in healthy tissue.
This is the first study that links the Wnt pathway with disrupted myelin repair in people with MS, and the discovery may offer inroads to finding ways to stimulate stalled myelin repair. Further study, which is ongoing, is needed to understand the interactions necessary for myelin repair and how they might be malfunctioning in MS. The team is continuing to follow leads on other genes they found to be active during myelin repair, in hopes of identifying specific targets for the development of therapies to reverse the damage caused by MS.
In addition to National MS Society support, this study also received funding from the MS Society of the United Kingdom and Northern Ireland, the National Institutes of Health and the Howard Hughes Medical Institute.
Read more about National MS Society-supported research aimed at repairing nervous system damage in MS.