Schwann cells in the regenerating fish optic nerve: Evidence that CNS axons, not the glia, determine when myelin formation begins

Fish optic nerve fibres quickly regenerate after injury, but the onset of r emyelination is delayed until they reach the brain. This recapitulates the timetable of CNS myelinogenesis juring development in vertebrate animals ge nerally, and we have used the regenerating fish optic nerve to obtain evide nce that it is the axons, not the myelinating glial cells, that determine w hen myelin formation begins. In fish, the site of an optic nerve injury bec omes remyelinated by ectopic Schwann cells of unknown origin. We allowed th ese cells to become established and then used them as reporters to indicate the time course of pro-myelin signalling during a further round of axonal outgrowth following a second upstream lesion. Unlike in the mammalian PNS, the ectopic Schwann cells failed to respond to axotomy and to the initial o utgrowth of new optic axons. They only began to divide after the axons had reached the brain. Shortly afterwards, small numbers of Schwann cells began to leave the dividing pool and form myelin sheaths. More followed graduall y, so that by 3 months remyelination was almost completed and few dividing cells were left. Moreover, remyelination occurred synchronously throughout the optic nerve, with the same time course in the pre-existing Schwann cell s, the new ones that colonised the second injury, and the CNS oligodendrocy tes elsewhere. The optic axons are the only common structures that could sy nchronise myelin formation in these disparate glial populations. The respon ses of the ectopic Schwann cells suggest that they are controlled by the re generating optic axons in two consecutive steps. First, they begin to proli ferate when the growing axons reach the brain. Second, they leave the cell cycle to differentiate individually at widely different times during the en suing 2 months, during the critical period when the initial rough pattern o f axon terminals in the optic tectum becomes refined into an accurate map. We suggest that each axon signals individually for myelin ensheathment once it completes this process.