"The investigation, conducted in mice and in human tissue, showed that repair of nerve fibers is hampered by biochemical signals that inhibit the development of cells known as oligodendrocytes, which function as repair workers in the brain.
Oligodendrocytes form a protective sheath, known as myelin, that insulates the fibrous cables, or axons, radiating from nerve cells. In multiple sclerosis, the immune system's T cells and B cells attack oligodendrocytes, ultimately damaging the myelin sheath to the point that the electrical signals transmitted by the axons beneath it are disrupted.
Remarkably, the brain generally is able to recruit fresh, immature oligodendrocytes to the myelin sheath to repair the damage, for a time. This explains why, in the most common form of the disease, known as relapsing remitting MS, the symptoms -- which range from tingling and numbness in the limbs to loss of vision and paralysis -- disappear or are greatly reduced, for some times months or years at a time.
Ultimately, however, the repair process falters and the disease progresses. In their study, the team set out to see if they could determine what was slowing down myelin repair. They lesioned a small region of white matter in healthy mice, then monitored the repair process, examining the tissue after five, 10, and 14 days.
To find out which genes were contributing to three key stages in the repair process – the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- they measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.
The team then honed in on a gene called Tcf4, because its expression was strong in damaged areas where repair attempts were under way.
Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced "wint") pathway, whose importance has been well recognized in normal development of many tissues, including the brain. Until now, however, Wnt had not been linked to myelin production or repair.
"This is the first evidence implicating the Wnt pathway in multiple sclerosis," says lead author Stephen P.J. Fancy, PhD, a postdoctoral fellow in the Rowitch lab. "We consider this an exciting development in our efforts to understand why the repair process often fails in the disease."