In the adult mammalian central nervous system (CNS), axonal injury leads to retrograde neuronal degeneration and death in cell soma.1,2) For instance, transection of the rat optic nerve (ON) induces cell death of retinal ganglion cells (RGCs) within 2 weeks. 3,4) In contrast, injury to the fish ON never leads to widely spreading death of RGCs. Goldfish regrow the axons of their RGCs towards the tectum and finally restore their vision, even after ON transection. 5,6) It has been shown that some rat RGCs can regenerate their axons through peripheral nerve grafts.7) This result implies that the inability of CNS neurons to regenerate in mammals is mainly due to a surrounding inhibitory environment, but not to the nature of the neurons themselves. Therefore, two approaches to the reconstruction of injured ONs in mammals have been studied intensively: 1) the use of nerve grafts or transplantation of stem cells [8][9][10] and 2) studying the regeneration mechanism of the mammalian peripheral nervous system (PNS) and fish CNS.11-13) Our goal here is aimed to introduce the works of goldfish ON regeneration after injury and show up the difference between fish and mammals.Since the first description of fish ON regeneration by Sperry's group in the 1950s, there has been a significant increase in the understanding of morphological changes in RGCs and factors which promote neurite outgrowth in optic axons after ON transection. In contrast, there is little knowledge regarding the molecular (genetic) mechanisms and cellular signaling pathways involved in fish ON regeneration after injury. Very recently, we apply a molecular cloning technique to find out ON regenerating molecules in goldfish after nerve injury. We obtain cDNA clones that are upregulated in the fish retina and tectum during ON regeneration. In this article, we review the neurite outgrowth-promoting factors reported by other investigators and our strategies for searching ON regenerating molecules in the goldfish visual system after injury.
MORPHOLOGICAL ASPECTS OF FISH ON REGENER-ATIONIn goldfish, unmyelinated sproutings occur at the cut end of the ON within 3 d, and then bundles of 20-30 axonal sproutings penetrate into the cutting edge by 6 d after ON lesion.14) Outgrowth of the leading axons proceeds at 0.3 mm/d after axotomy.15) The regenerating fibers first reach the optic lobe at 10-12 d after ON lesion, and the plexiform layer formed by the regenerating fibers is visible in all areas of the optic tectum at 14-18 d after ON lesion.16) Although the retinotectal connection is formed 20-40 d after ON section, the regenerated retinotectal projection lacks topographic order for up to 40 d. Thereafter, the retinotectal topography slowly improves over several months.17) Thus, the retinotectal connection is initially very rough and then becomes very refined after a long time. This refinement process of the regenerating fibers can be traced using local injections of wheat germ agglutinin conjugated to horse radish peroxidase (WGA-HRP) in the retina. After goldfish ON...