Diekmann, H., Klinger, M., Oertle, T., Heinz, D., Pogoda, H.M., Schwab, M.E., and Stuermer, C.A. (2005) Analysis of the Reticulon Gene Family Demonstrates the Absence of the Neurite Growth Inhibitor Nogo-A in Fish. Mol. Biol. Evol.. 22(8):1635-1648.
Reticulons (RTN) are a family of evolutionary conserved proteins with four RTN paralogs (RTN1, RTN2, RTN3, RTN4) present in land vertebrates. While the exact functions of RTN1 - RTN3 are unknown, mammalian RTN4-A/Nogo-A was shown to inhibit the regeneration of severed axons in the mammalian central nervous system (CNS). This inhibitory function is exerted via two distinct regions, one within the Nogo-A specific N-terminus and the other in the conserved reticulon homology domain (RHD). In contrast to mammals, fish are capable of CNS axon regeneration. We performed detailed analyses of the fish rtn gene family to determine whether this regeneration ability correlates with the absence of the neurite growth inhibitory protein Nogo-A. Seven rtn genes were identified in zebrafish, six in pufferfish and 30 in 8 additional fish species. Phylogenetic and syntenic relationships indicate that the identified fish rtn genes are orthologs of mammalian RTN1, RTN2, RTN3 and RTN4 and that several paralogous fish genes (e.g. rtn4 and rtn6) resulted from genome duplication events early in actinopterygian evolution. Accordingly, sequences homologous to the conserved RTN4/Nogo RHD are present in two fish genes, rtn4 and rtn6. However, sequences comparable to the first approximately 1000 aa of mammalian Nogo-A including a major neurite growth inhbitory region are absent in zebrafish. This result is in accordance with functional data showing that axon growth inhibitory molecules are less prominent in fish oligodendrocytes and CNS myelin compared to mammals.