Axons of Amphibian and Fish Optic Nerve

FIGURE 5.11 Effects of growth factors on explants of axolotl spinal cord tissue. (A, B) Medium containing TGF-P and EGF (TPE) supports ependymal outgrowth at 0 days (0D) and 6 days. (C-F) TGF-P (T) and PDGF (P) cause ependymal explants to break apart and disperse on the dish as cords of cells over a six-day period in culture. Courtesy of Dr. Ellen Chernoff.

FIGURE 5.11 Effects of growth factors on explants of axolotl spinal cord tissue. (A, B) Medium containing TGF-P and EGF (TPE) supports ependymal outgrowth at 0 days (0D) and 6 days. (C-F) TGF-P (T) and PDGF (P) cause ependymal explants to break apart and disperse on the dish as cords of cells over a six-day period in culture. Courtesy of Dr. Ellen Chernoff.

been shown to be important for peripheral nerve regeneration would presumably also be involved in urodele spinal cord regeneration, but this question has not yet been addressed.

An important feature of cord injury in amphibians is that myelin proteins inhibitory to spinal cord regeneration in mammals appear not to be present or to be removed. Nogo is not present in the regenerating cord of fish and larval Xenopus, although other molecules such as MAG, CSPGs and tenascin-R are present but do not inhibit regeneration (Wanner et al., 1995; Lang et al., 1995; Becker et al., 1999). Tenascin-R and MAG are rapidly removed in injured adult newt spinal cord (Becker et al., 1999), probably by macrophages ingesting fragments of myelin. The presence and disposition of these molecules have not yet been studied in the regenerating cord of other urodeles. In metamorphosing Xenopus, spinal cord myelin becomes nonpermis-

The optic nerve is a cranial nerve that forms by extension of axons from the ganglion cell layer of the neural retina to the optic tectum of the brain. Mammals cannot regenerate the transected or crushed optic nerve, a failure that is related to astrocytic reactive gliosis and early postnatal downregulation of the apop-tosis inhibitor Bcl-2 (Cho et al., 2005). Adult fish and larval and adult amphibians, however, can regenerate their optic nerves and are therefore good models with which to identify regeneration-permissive conditions (Matthey, 1925; Sperry 1944; Gaze, 1959; Attardi and Sperry, 1963). The original connections of the optic nerve to the tectum are re-established in these animals and vision is recovered.

In contrast to the mammalian optic nerve, spinal cord or brain, where astrocytes help form a glial scar that impedes axon extension, the astrocytes of the optic tract promote axon extension in the adult newt and in Xenopus tadpoles (Reier and Webster, 1974; Turner and Singer, 1974; Stensaas and Feringa, 1977; Reier, 1979; Scott and Foote, 1981; Bohn et al., 1982). The astrocytes in the degenerated distal portion of the cut optic nerve hypertrophy and form a longitudinal band within the basement membrane synthesized by the pia mater (Turner and Singer, 1974; Bohn et al., 1982). These astrocytes are different from those of mammals in that they do not express GFAP, but do express nestin and cytokeratin intermediate filaments and desmo-somal proteins (Rungger-Brandle et al., 1989).

The growth cones of the regenerating optic nerve axons associate preferentially with end-feet of the astro-cytes that project toward the pia, so all the regenerating axons are found just under the pia (Gaze and Grant, 1978; Bohn et al., 1982). Eliminating the astrocyte band by resection of a segment of the optic nerve results in a decrease in the number of regenerating axons crossing the lesion into the nerve stump and an increase in the number of axons deviated into inappropriate locations (Bohn et al., 1982). Thus, the astrocytes of the regenerating amphibian optic nerve appear to support axon regeneration in the same way that ependymal cells support the regeneration of spinal cord axons and Schwann cells support the regeneration of spinal nerves in mammals.

Studies on goldfish optic nerve regeneration suggest that the regenerating axons and glial cells of the optic tract in fish and amphibians require at least some of the same molecules required for axon sprouting and elongation as do spinal nerve axons in mammals. The optic nerves of goldfish have good capacity for regeneration (Attardi and Sperry, 1963), with visual recovery occur-ing by 5-6 weeks (Edwards et al., 1981). RNA and protein synthesis are significantly elevated in goldfish retinal ganglion neurons during regeneration, and provide growth-associated proteins that are transported down the length of successfully regenerating axons (Grafstein, 1991; Stuermer et al., 1992). Cell adhesion and basement membrane molecules are associated with optic nerve regeneration, but these have not yet been shown to be made by optic nerve astrocytes. The adhesive substrate preferred by regenerating optic nerve axons of stage 47-50 Xenopus tadpoles is laminin, followed by collagen I > polylysine = polyornithine > fibro-nectin (Grant and Tseng, 1986). The retinal ganglion cells of regenerating goldfish optic nerve express GAP-43 and NCAMs (Stuermer et al., 1992) and two other surface proteins called reggie-1 and 2 (Schulte et al., 1997) that probably interact with the surface of the optic nerve astrocytes.

The ability to regenerate the optic nerve in fish and amphibians is also associated with the absence of inhibitory myelin proteins in the lesion. Tenascin-R and MAG are removed from the degenerated optic nerve in the newt, probably by macrophages, as in regenerating spinal nerves of mammals (Becker et al., 1999). Cohen et al. (1990) reported that goldfish optic nerves produce a factor that is cytotoxic to myelin-producing oligodendrocytes. The factor is recognized by antibodies to the growth factor IL-2, and its size indicates that it might be a dimer of IL-2 (Eitan and Schwartz, 1993). Consistent with this hypothesis, an enzyme identified as a nerve transglutaminase was purified from regenerating optic nerves of fish, and was shown to dimerize human IL-2. The dimerized IL-2 was cytotoxic to cultured rat brain oligodendrocytes. Thus the transglu-taminase-catalyzed dimerization of IL-2 might be a mechanism in the fish and amphibian optic nerve that prevents oligodendrocyte inhibition of regeneration.

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