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Cone Photoreceptor Regeneration in Adult Fish Retina: Phenotypic Determination and Mosaic Pattern Formation

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Cone Photoreceptor Regeneration in Adult Fish Retina: Phenotypic Determination and Mosaic Pattern Formation The Journal of Neuroscience, March 1995, E(3): 2255-2271 Cone Photoreceptor Regeneration in Adult Fish Retina: Phenotypic Determination and Mosaic Pattern Formation David A. Cameron and Stephen S. Easter, Jr. Department of Biology, University of Michigan, Ann Arbor, Michigan 48109-1048 The retina of anamniotes (fish and amphibia), unlike the (1926), who transplantedwhole eyes of urodele amphibians,and CNS of most vertebrates, can regenerate neurons following showed that the restoration of vision occurred after a complete injury. Using the highly ordered mosaic of single and dou- degeneration, then regeneration, of the neural retina. Sperry ble cones in the retina of the adult green sunfish (Lepomis (1949) showed that fish retina could do the same,and Wolburg cyanellus) as our model system, we examined the events and Raymond and their collaborators (e.g., Maier and Wolburg, that followed the surgical excision of a small patch of cen- 1979; Raymond et al., 1988) have extended this work. tral retina. After surgery there was a transient elevation in Regeneration of fish neural retina also occurs following the the number, and a change in the distribution, of prolifera- surgical removal of a small patch. Hitchcock et al. (1992) dem- tive cells within the retina. The wound was filled in two onstrated that an excised patch is filled epimorphically, as a re- ways: a proliferative regeneration of new retina and a non- sult of mitotic activity in a population of proliferative cells that proliferative movement of the wound boundaries toward forms along the perimeter of the wound. This wound blastema the center of the lesion. The nonproliferative movement resemblesthe proliferative neuroepithelium (the marginal ger- stretched the surrounding, intact retina. In stretched retina minal zone) that encircles the retina (Hitchcock et al., 1992; the basic pattern of the cone mosaic was maintained, but MacDonald et al., 1994), but the two proliferative zones are it was augmented by new cones, even though cones are oriented differently. As cells in the marginal germinal zone pro- not normally generated in intact central retina. The stretch liferate, their postmitotic daughter cells remain central to the itself likely triggered the anomalous cone production. The retinal margin, and the proliferative stemcells are displacedcen- new and preexisting cones in stretched retina had their trifugally as part of an ever-increasingretinal perimeter. In con- morphological phenotypes influenced by mutual contact, trast, the stem cells of the wound blastema are displaced cen- often resulting in atypical morphologies (triple and quad- tripetally, toward the center of the wound, and their postmitotic ruple cones). In the center of the lesioned area, the regen- daughter cells remain outside the wound perimeter to form the erated cone mosaic was disordered, had a higher than nor- regeneratedneural retina. mal cone density, and contained atypical morphologies. Studiesof epithelial wound healing have describeda different, The presence of outer segments and synaptic pedicles nonproliferative mechanismfor filling in the wound that may suggested that the new cones in regenerated and stretched affect neural regeneration in the fish retina. When a patch of retina were functional. We interpret these results to mean embryonic chick skin is surgically removed, the perimeter of the (1) a stretch-induced decrease in cell density can trigger a wound is partially reduced by a purse-string-like closure caused compensatory, adaptive neurogenesis, (2) cone morpho- by the contraction of an actin belt that rapidly forms aroundthe logical phenotypes in fish retina are plastic throughout life, lesion (Martin and Lewis, 1992). If the filling-in of a retinal and are influenced by cone-cone contacts, (3) the mecha- wound involves a similar, nonproliferative inward spreadof the nisms that spatially regulate cone production during nor- wound boundaries,then the intact retina surrounding the lesion mal growth are disrupted during regeneration. must be stretched. This stretch would reduce the planimetric [Key words: regeneration, retina, neurogenesis, photo- density of the retinal cells in the area surrounding the wound, receptors, fish, cones] becausethe samenumber of cells would be spreadover a greater area. Such a reduction would be of interest becausethe plani- The CNS of anamniotes(fish and amphibia) has remarkable metric density of retinal cells is functionally important, partic- powers of repair and regeneration,and one of the most remark- ularly in the photoreceptor layer, where rods and cones cover able is their ability to regenerate whole new tissue. This has the retinal lawn to maximize the capture of incident light. If a been best documented in the neural retina, first by Matthey surgical lesion causesthe retina to stretch suddenly (as distinct from the slow stretch that accompaniesnormal retinal growth; Received Aug. 5, 1994; revised Sept. 14, 1994; accepted Sept. 28, 1994. Ali, 1964; Johns and Easter, 1977), then perhaps new cells are We thank Celeste Malinoski for technical assistance, Dr. Kathy Tosney for generatedto compensatefor the reduction in density. Interstitial the cryosection protocol, and Drs. Laurel Carney, Grant Mastick, Charlotte insertion of new neuronsinto an intact nervous systemis intrin- Mistretta, and Pamela Raymond for their comments on the manuscript. This work was supported by NIH Grants EY-00168 (S.S.E.) and F32 EY-06469 sically interesting, and may have long-rangeclinical importance. (D.A.C.), and a Sokol &stdoctoral Award (D.A.C.). This article studiesthe sequelsto removal of a small patch of Correspondence should be addressed David A. Cameron, Department of Bio- adult green sunfishretina, with particular attention to the region medical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215-2407. surrounding the wound. In this endeavor we have taken advan- Copyright 0 1995 Society for Neuroscience 0270.6474/95/152255-17$05.00/O tage of the very orderly mosaic of cone photoreceptors(Cam- 2256 Cameron and Easter l Cone Regeneration in Adult Fish Retina Figure 1. Schematic diagram of the surgical procedures (ad) and photomicrograph of a lesioned retina in whole-mount (e). a, Three transscleral incisions into the eye made with a microknife. b, Flap of tissue produced in a is pulled down and the underlying retina and pigmented epithelium are removed. c, Remaining flap of sclera is sutured to neighboring sclera. d, Following sacrifice and fixation, two crystals of DiI (arrows) are applied to the exposed face of a cut optic nerve. e, Whole-mount of retina and pigmented epithelium, retina side up, viewed with epifluorescence microscopy. DiI-labeled retinal ganglion cell (RGC) axons extend outward from the optic papilla, at the center of the whole-mount, and terminate in annuli of RGC somata. The annuli are interrupted (arrows) at the lateral edges of a lesion site produced 78 d earlier. An extrusion of darkly pigmented material is present near the center of the lesion. Angular distances from one of the lateral lesion edges, 30” in width, are indicated. N, nasal; D, dorsal; T, temporal; V ventral. eron and Easter, 1993). We report that the intact retina surround- slit incision was made through one retina, and the other was unoperated. ing a wound is stretched by a nonproliferative spread into the These fish survived 8, 14, or 45 d. Cone mosaic analysis: whole-mounts. Following sacrifice, both eyes lesion. Within stretchedretina, the cone mosaicis augmentedby were enucleated and the corneas and lenses were removed. The resulting the interstitial addition of new cone cells, a neural cell type that eye cups were fixed by immersion in 4% paraformaldehyde in 0.05 M is not normally generatedin central, intact retina. The assembly PO, buffer overnight. One or more small pellets of the fluorescent car- of the cone mosaic, the determination of cone phenotype, and bocyanine dye DiI (l,l’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocy- anine perchlorate; Molecular Probes, Eugene, OR; Honig and Hume, the replacementof neurons in the adult CNS are discussed. 1986; Godement et al., 1987) were embedded within the cut face of the optic nerve (n = 13), and the eye cups were incubated in fixative at Materials and Methods 45°C for 5 d. DiI was incoruorated into retinal aanelion cell (RGC) Adult green sunfish (Lepomis cyanellus, n = 32) were purchased from axonal membranes local to the pellet, and retrogGde?y labeled annuli Fender’s Fish Hatchery and Llama Farm (Baltic, OH). Animal hus- of RGC somata and dendrites (Easter, 1992; Cameron and Easter, 1993), bandry, anesthesia, and euthanasia techniques were as described pre- and one of these annuli generally intersected the lesion site or lay pe- viously (Cameron and Easter, 1993). Fully light adapted fish were used ripheral to it. Retinal whole-mounts were made with the pigment epi- in all procedures. thelium side down, cover slipped with 50% glycerol, 50% PO, buffer, Retinal surgery. Small transscleral excisions were made of dorsotem- and viewed with epifluorescence microscopy. Cone mosaics were vi- poral retina and pigmented epithelium of one eye (Hitchcock et al. sualized by focusing through the whole-mounts. 1992); the other eye was unoperated (n = 25). The excisions were The lateral edgesof the-lesions were visualized as gaps within the roughly square and approximately 2-4 mm* in area (Fig. la-d). These annuli of D&labeled RGC somata and dendritic fields (Fig. le). Such fish survived for 2-430 d. In other
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