Previous experiments have shown that nerve growth factor (NGF) enhances regeneration of goldfish optic nerve after local application of NGF at the site of the lesion. However, the site and mechanism of action of NGF are not yet known. One possibility is that NGF is taken up at the site of the lesion and retrogradely transported to the cell bodies of the retinal ganglion cells and thereby exerts its trophic effects. The present work was carried out to assess the role of retrograde transport of NGF in this enhanced regeneration of goldfish retinal ganglion cells. In intact retinal ganglion cells of the goldfish, 125I-labeled NGF was found not to be retrogradely transported from the optic tectum to the retina, suggesting that retinal ganglion cells do not possess specific NGF receptors. However, if [125I]NGF was injected at the site of an optic nerve lesion at the time of lesion, [125I]NGF was retrogradely transported from the site of a lesion of the optic nerve to the cell body of retinal ganglion cells. The accumulated radioactivity was shown to be intact NGF by SDS-PAGE. The ability of NGF to decrease the time required for recovery of visual function was observed only when NGF was administered at the time of the injury. Likewise, no transport of [125I]NGF was observed when it was injected at the crush site 16 hr or longer after crush. Thus, there is a temporal correlation between the ability of intact [125I]NGF to be retrogradely transported from a lesion site to the retina and the regenerative effect of NGF. Autoradiography showed that the [125I]NGF accumulated only in retinal ganglion cells. The transport of NGF in the lesioned goldfish visual system was not specific for NGF in that other proteins (cytochrome c, bovine serum albumin) were transported equally well. Likewise, transport of [125I]NGF was not prevented by concomitant administration of excess unlabeled NGF. The retrograde transport of [125I]NGF therefore was not selective and did not appear to be mediated by specific NGF receptors in this system. This nonspecific transport of [125I]NGF did not occur in the axotomized spinal motor neurons in the neonatal or adult rat or in the newt. However, receptor-mediated transport is seen in lesioned sensory neurons in both species.(ABSTRACT TRUNCATED AT 400 WORDS)