Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule

Many factors have been shown to promote myelination, but few have been show n to be inhibitory. Here, we show that polysialylated-neural cell adhesion molecule (PSA-NCAM) can negatively regulate myelin formation. During develo pment, PSA-NCAM is first expressed on all growing fibers; then, axonal expr ession is downregulated and myelin deposition occurs only on PSA-NCAM-negat ive axons. Similarly, in cocultures of oligodendrocytes and neurons, PSA-NC AM expression on axons is initially high, but decreases as myelination proc eeds. Importantly, if expression of PsA-NCAM is prematurely decreased in cu ltures, by either antibody-mediated internalization or enzymatic removal of the PSA moieties with endoneuraminidase N (endo-N), myelination increases 4- to 5-fold. In the optic nerve, premature cleavage of PSA moieties by int ravitreous injection of endo-N also induces a transient increase in the num ber of myelinated internodes. but does not interfere with the onset of myel ination. Previously, we showed that axonal electrical activity strongly ind uced myelination, which could be prevented by tetrodotoxin (TTX), an action potential blocker. Interestingly, removal of PSA moieties does not reverse the inhibition of myelination by TTX. Together, this suggests that myelina tion is tightly controlled by both positive (electrical activity) and negat ive (PSA-NCAM expression) regulatory signals.