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Distribution of Photoreceptor Subtypes in the Retina of Diurnal and Nocturnal Primates

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Distribution of Photoreceptor Subtypes in the Retina of Diurnal and Nocturnal Primates The Journal of Neuroscience, October 1990, IO(10): 33904401 Distribution of Photoreceptor Subtypes in the Retina of Diurnal and Nocturnal Primates Kenneth C. Wikler and Pasko Rakic Section of Neuroanatomy, Yale University School of Medicine, New Haven, Connecticut 06510 We have used antibodies specific to either the red/green- mately enhance our understanding of normal and abnormal or blue-sensitive cones in order to compare their ratio and color vision in humans (e.g., Greenstein et al., 1989). distributions to that of the rods in the retinae of 3 primate The relationship between color vision and the photoreceptor species that differ in their capacity for color vision. We have mosaichas been studied most frequently in Old-World macaque found that the monoclonal antibody CSA-1 (Johnson and monkeys (Daw, 1984). These are diurnal speciesthat have a Hageman, 1988) and the polyclonal antibody 4942A, specific distinct fovea and a topographic distribution of rods and cones to the red- and green-cone opsin (Lerea et al., 1989), applied that is similar to that ofhumans (e.g., Jacobs, 1981,1986; Curcio to retinal whole-mounts labeled approximately 90% of all et al., 1987, 1990; Packer et al., 1989; Wikler et al., 1990). In cones in the diurnal Old-World rhesus monkey (Maccaca contrast, our knowledge about photoreceptors and color vision mulaffa) and all of the cones in the nocturnal New-World owl in New-World monkeys and prosimians is fragmentary. These monkey (Aotus trivirg8fu.s) and nocturnal prosimian bush- speciesoffer the opportunity to compare the retinae of primates baby (Galago garnet@. The polyclonal antibody 1088, spe- that differ in their visual capacity or phyletic relatednessto either cific to the blue-cone opsin (Lerea et al., 1989), labeled about macaquesor humans. For example, the owl monkey, which is 10% of the cones across the entire surface of the rhesus the only living nocturnal anthropoid, haspoorly developedcolor monkey retina, but failed to label any cones in the retina of vision that is similar to that of protanomalous humans(Jacobs, the 2 nocturnal species. Only the retina of the rhesus monkey 1977a,b). There are only a few reports concerning color vision possessed an all-cone foveola in which the density of cone in nocturnal prosimians (Dartnall et al., 1965; Casagrandeand inner segments was 17-fold greater than that in the fovea DeBruyn, 1982). These speciesare of considerableinterest be- of the owl monkey or bushbaby retina. Surprisingly, the den- cause they are an evolutionarily conservative group and may sity of cones per unit area outside of the fovea was com- retain many characteristicsof ancestorsthat are also common parable in all 3 species. Rod density in the dorsal retina was to monkeys, apes, and humans (Allman, 1978; Blakesleeand elevated in all animals examined, but was 2-3 times greater Jacobs, 1985). in the nocturnal species than in the rhesus monkey retina. Traditionally, studiesof the number and distribution of pho- Application of the photoreceptor-class-specific antibodies toreceptors in macaqueshave relied on morphological distinc- may provide further insights into the evolution and devel- tions such as the position of nuclei and the length, width, and opment of wavelength sensitivity in the retina, as well as shape of the outer and inner segments(Ahnelt et al., 1987). enhance our understanding of normal and abnormal color However, studiesof photoreceptor distribution in nocturnal an- vision in humans. thropoids and prosimians have proved difficult becausecom- monly used morphological criteria cannot reliably distinguish The primate photoreceptor mosaic consists of 4 functionally between photoreceptor subtypes. distinct cell populations: the rods, which mediate scotopic vi- In the past decade, immunologic markers have been devel- sion, and 3 cone subtypes, which mediate photopic and color oped that can distinguish between different photoreceptor sub- vision (e.g.,Jacobs, 198 1; Rodieck, 1988).The 3 classesof cones types. Initial antisera could only discriminate between rods and are distinguished by the presenceof pigments that are prefer- cones(Bamstable, 1980, 1987; Balkema and Drager, 1985;Aka- entially sensitive to short (blue-sensitivecones), middle (green- gawa and Barnstable, 1986; Lemon, 1986). However, more re- sensitive cones), or long (red-sensitive cones) wavelengths of cently, antibodiesto different cone subtypeshave beengenerated light (Schnapf et al., 1987). Knowledge about the distribution (e.g., Szel et al., 1988; Muller et al., 1989). In the present study, of these photoreceptor subclassesin diurnal and nocturnal pri- we have used several antisera to different photoreceptor sub- matescould provide insight into the development, inheritance, types to examine their distribution. One of theseis the monoclo- and evolution of wavelength sensitivity in the retina and ulti- nal antibody CSA- 1, which was initially reported to label only membranesof cones in the pig retina (Johnson and Hageman, 1988). Further studies indicate that CSA-1 selectively labels Received Apr. 4, 1990; revised May 31, 1990; accepted June 7, 1990. both red- and green-sensitivecones, but not blue-sensitivecones, This research was supported by U.S. Public Health Service grant EY 02593 (P.R.) and Postdoctoral Fellowship NS 0859-01 (K.C.W.). We are grateful to Jim in the rhesusmonkey (Wikler and Rakic, 1989)and pig (Rohlich Hurley, Lincoln Johnson, and Connie Lerea for generously providing the anti- et al., 1989) retina. We have also used antisera raised against bodies, Richard Cameron for advice and useful suggestions, and Todd Preuss and synthetic peptides generated from amino acid sequencesfor Michael Schwartz for comments on the manuscript. Correspondence should be addressed to Dr. Kenneth C. Wilder, Section of cDNAs of human photopigment polypeptides (Nathans et al., Neuroanatomy, Yale University School of Medicine, New Haven, CT 065 10. 1986; Lerea et al., 1989). Thesepolyclonal antibodiesselectively Copyright 0 1990 Society for Neuroscience 0270-6474/90/103390-12$03.00/O label red- and green-sensitivecones or blue-sensitive cones in The Journal of Neuroscience, October 1990, fO(10) 3391 the human retina (Lerea et al., 1989). Our use of these antisera were converted into local densities by calculating the number of either allow us, for the first time, to examine not only the ratio and rods or cones per square millimeter. distribution of rods versus cones, but also to assess the presence Results or absence of wavelength-sensitive cone subtypes. Rhesus monkey In the present study we have sought to determine: (1) whether all cone subtypes are present in nocturnal anthropoid and pro- The useof DIC optics allowed clear discrimination betweenrod simian species, and if so, what are their cytological character- and cone outer segmentsin unstained and unreacted whole- istics, dimensions, and pattern of distribution; and (2) how the mounts of the macaqueretinae (Fig. 1A). The diameter of cone outer and inner segmentsat any particular retinal eccentricity, distribution of photoreceptor subtypes is related to visual ca- pacity in these 3 species (i.e., nocturnal vs diurnal). outside of the rod-free foveola, was consistently larger than the diameter of rod outer and inner segments(Fig. 1A). This distinct Materials and Methods difference in size between rod and cone photoreceptors in the rhesusmonkey enabled usto independently and unambiguously Tissue preparation. Eyes from 4 rhesus macaque monkeys (Macaca confirm the cellular specificity of the antibodies. mulatta), 4 owl monkeys (Aotus trivirgatus), and 4 thick-tailed bush- babies (Galago garnetti) were used for this study. Animals were deeply In the rhesus monkey, CSA-1 and 4942A labeled cones ex- anesthetized with ketamine and sodium pentabarbitol prior to enucle- clusively; we did not observe immunoreactivity in any rod pro- ation, then killed for unrelated experiments. The retinae were dissected files acrossthe entire retinal surface (Fig. 2A,B). However, in free from other tissue layers of the eyes, marked for orientation, and addition to an absenceof labeled rods, we observed a regular briefly fixed in 4% paraformaldehyde in 0.1 M phosphate buffer (Stone, 1981). and periodic absenceof CSA-1 or 4942A labeling in a small Zmmunohistochemistry. Immersion-fixed retinae were rinsed in 0.1 proportion of profiles across the photoreceptor mosaic whose M phosphate buffer (pH, 7.4) prior to overnight incubation in 1 of 3 large outer segmentsclearly identified them as a subpopulation antisera:GA-l, a mousemonoclonal antibody diluted 1: 1000 with of cones (Fig. 2A,B). An average of 10% of all coneswere un- 0.1% T&on-X 100 in 0.1 M phosphate buffer (pH, 7.4); 4942A, an labeledin the entire retina, and this value varied between about affinity-purified rabbit polyclonal antibody against the polypeptide se- quence for the green/red opsin diluted 1: 10 with 0.1% T&on-X 100 in 5% and 15% at different eccentricities. Additionally, the unla- 0.1 M phosphate buffer (pH, 7.4); or the 108B affinity-purified rabbit beled coneswere distributed in a regular pattern among labeled polyclonal antibody against the polypeptide sequence for the blue opsin cones. diluted 1: 10 with 0.1% T&on-X 100 in 0.1 M phosphate buffer (pH Analysis of the distribution of CSA-1 and 4942A immuno- 7.4). Following incubation in the primary antisera at 4°C retinae were reactivity revealed that, though the topography of labeledcones rinsed in 0.1 M phoosphate buffer (pH 7.4) and incubated in biotinylated anti-mouse or anti-rabbit IgG for 1 hr at 22°C. The retinae were rinsed was essentiallyidentical for both antibodies, the localization of in several changes of phosphate buffer, then incubated in an avidin- the reaction product within cones differed for these antisera. biotin-peroxidase complex (Vectastain, Vector Lab., Burlingame, CA) Immunoreactivity to the 4942A antibody was restricted to the for 1 hr. Retinaewere then reacted using diaminobenzidine (0.05% 3,3- cone outer segments.In contrast, the HRP reaction product in diaminobenzidine HCl and 0.003% H,O,).
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