Nogo-A/RTN-4A with its two inhibitory regions, Nogo-66 and the Nogo-A-specific region (NSR) blocks axon regeneration in the mammalian CNS, and even of fish axons in vitro. In fish, however, where lesioned axons in the CNS, such as optic nerve, do regenerate, Nogo-66 is not inhibitory and the NSR absent from RTN-4. Yet fish should possess a receptor for Nogo-A NSR, a reasonable assumption in light of our new data indicating that zebrafish RTN-6, a duplicate of RTN-4, contains an NSR homolog. Analysis of the evolution of Nogo-A and RTN-6 suggests that they originate from a chondroitin sulfate proteoglycan (CSPG) of ancient chordates. It shall be clarified whether fish retinal axons recognise not only mammalian NSR but also NSR of their own RTN-6 as an inhibitor of growth - through a specific (NSR) receptor or by blocking growth-promoting receptors (such as integrins) which can be expected by the similarity to CSPG. In addition, work towards the generation of a stable zebrafish transgenic line expressing the mammalian NSR in CNS glial cells will be continued, to ultimately decide whether Nogo-A, during evolution, has developed to the strongest inhibitor of axon growth which even might overcome the very growth-supporting conditions in the fish CNS.