Retinal ganglion cells (RGCs) in adult zebrafish can regenerate their axons. We show that successful axonal regeneration is accompanied by the re-expression by RGCs of mRNAs encoding specific recognition molecules that are expressed at high levels in the larval retina but are down-regulated in the adult. Message levels for 11.1 and 11.2 (two homologs of mammalian L1), n-cam (homologous to mammalian N-CAM), beta 3 (related to the beta 3 and beta 2 subunits of mammalian Na,K-ATPase), and tn-c (homologous to mammalian tenascin-C) were high in larval RGCs undergoing axonogenesis and low in adult RGCs. After an optic nerve crush, axotomized adult RGCs showed increased levels of 11.1, 11.2 and n-cam mRNA expression, whereas the levels of beta 3 and tn-cmRNA remained unchanged. The optic nerve crush also induced the expression of some of these mRNAs in the optic nerve and tract where they are not normally detectable. This lesion induced up-regulation by presumptive glia was observed for 11.1, 11.2, n-cam and beta 3 but not for tn-c. The combination of a neuronal (intrinsic) response to axotomy with an environmental (extrinsic) response may be an important determinant allowing for the successful axonal regeneration.