To devise strategies to repair damage in the adult mammalian central nervous system (CNS), it is essential to understand the cellular and molecular mechanisms that cause axonal regeneration to fail. The prevailing view is that axon-growth inhibitors in myelin, such as Nogo and myelin-associated glycoprotein, are the chief barriers to regeneration — a model that was comprehensively reviewed by Marie Filbin in the September 2003 issue of Nature Reviews Neuroscience. However, two articles in this issue call into question the dominance of this hypothesis.

On page 146, Miller and Silver highlight the role of the glial scar in regeneration failure. The scar forms in response to CNS injury, and it contains reactive astrocytes and proteoglycans. Although the scar might have benefits in terms of secluding the site of injury from healthy tissue and limiting the spread of tissue damage, it also has the less desirable effect of inhibiting axon growth. Miller and Silver describe how growth cones behave in the presence of the inhibitory scar components, and how we might overcome these effects to promote successful regeneration.

Clearly, this glial-scar model is not mutually exclusive with the idea of myelin inhibition, but on page 157, Raisman presents an altogether more controversial view of myelin. He points out that although myelin can undoubtedly inhibit axon growth when presented as a barrier in culture, axons travel profusely through myelinated tracts in vivo. He suggests that myelin actually facilitates axon growth through a repulsive mechanism that prevents branching and deviation, and that although blocking myelin inhibitors might induce localized axon sprouting, it might also prevent long-range regeneration. This model clearly requires further investigation, but if it proves to be valid, it could radically change our approach to CNS repair.