Retinoid X Receptor Is Necessary to Establish the S-Opsin Gradient In

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Retinoid X Receptor Is Necessary to Establish the S-Opsin Gradient In Retinoid X Receptor ␥ Is Necessary to Establish the S-opsin Gradient in Cone Photoreceptors of the Developing Mouse Retina Melanie R. Roberts,1,2 Anita Hendrickson,2 Christopher R. McGuire,2 and Thomas A. Reh2 PURPOSE. The retinoid X receptors (RXRs) are members of the tion, they also have demonstrated some isoform-specific family of ligand-dependent nuclear hormone receptors. One of functions. For example, RXR␣ heterodimerizes with retinoic these genes, RXR␥, is expressed in highly restricted regions of acid receptors (RARs) to regulate retinal growth and cardiac the developing central nervous system (CNS), including the development.4 retina. Although previous studies have localized RXR␥ to de- Although all three isoforms are expressed in the developing veloping cone photoreceptors in several species, its function nervous system, RXR␥ has the most restricted and develop- in these cells is unknown. A prior study showed that thyroid mentally regulated expression. It is expressed in the develop- hormone receptor ␤2 (TR␤2) is necessary to establish proper ing striatum, part of the tegmentum, the pituitary, the ventral cone patterning in mice by activating medium-wavelength (M) horns of the spinal cord,3,5 and the retina.6 RXR␥-null mice cone opsin and suppressing short-wavelength (S) cone opsin. show isoform-specific defects in both striatal and hippocampal Thyroid hormone receptors often regulate gene transcription function, although RXR␤ can partially compensate for the loss as heterodimeric complexes with RXRs. of RXR␥ in the striatum.2,7,8 RXR␥ has also been identified in 6,9,10 METHODS. To determine whether RXR␥ cooperates with TR␤2 the developing retina of Xenopus, chicks, and mice. It has to regulate cone opsin patterning, the developmental expres- a highly restricted pattern of expression; and, in both chicks ␥ sion of RXR␥ was examined, and cone opsin expression in and mice, RXR is expressed in developing cones. Despite the RXR␥-null mice was analyzed. conserved expression pattern in developing cone photorecep- ␥ ␥ tors, the function of RXR in cone development is not known. RESULTS. RXR was expressed in postmitotic cones and was We have shown that thyroid hormone receptor ␤2 (TR␤2), transiently downregulated at the time of S-opsin onset in both ␥ another member of the same family of nuclear hormone recep- mouse and human cones. RXR -null mice expressed S-opsin in tors, has a role in the developmental “choice” of which opsin all cones, similar to the TR␤2-null mice. Unlike TR␤2-null mice, 11 ␥ gene to express. Like most mammals, mice have two opsin which did not express M-opsin, RXR -null mice had a normal proteins that respond maximally to different wavelengths: S- pattern of M-opsin expression. opsin to short wavelengths and M-opsin to longer wavelengths. CONCLUSIONS. RXR␥ is essential (along with TR␤2) for suppress- However, the ratio and distribution of cone opsins varies dra- ing S-opsin in all immature cones and in dorsal cones in the matically among species (for review, see Ref. 12). For example, mature retina, but it is not necessary for M-opsin regulation. S-opsin is excluded from the central fovea of human reti- These results demonstrate a critical role for RXRs in regulating nas.13,14 In mice, however, there is an opposing gradient of M- cell differentiation in the CNS and highlight a remarkable and S-opsin, so that M-opsin expression is highest in dorsal conservation of opsin regulation from Drosophila to mammals. cones, whereas S-opsin predominates in the ventral retina.15 (Invest Ophthalmol Vis Sci. 2005;46:2897–2904) DOI: TR␤2-null mice show a profound disruption in the cone opsin 10.1167/iovs.05-0093 gradient. In these mice, M-opsin is not expressed in any cones, indicating that TR␤2 is necessary to upregulate M-opsin. In he retinoid X receptors (RXRs) are members of the family addition, all cones in TR␤2-null mice express S-opsin, which Tof ligand-dependent nuclear hormone receptors that regu- indicates that TR␤2 is also necessary to suppress S-opsin. Be- late gene expression either as homodimers or more frequently cause TRs often regulate transcription as heterodimers with as heterodimeric complexes with other nuclear hormone re- RXRs, we hypothesized that RXR␥ may also play a part in the ceptors (for review, see Ref. 1). Studies of mice with targeted determination of cone opsin expression. gene mutations in each of the three RXR isoforms—␣, ␤, and To determine whether RXR␥ is necessary for proper cone ␥—have demonstrated that RXRs regulate several developmen- photoreceptor development, we examined the expression of tal processes, including cardiogenesis and neurogenesis.2,3 Al- RXR␥ during retinal development and analyzed the cone phe- though these studies have revealed some redundancy of func- notype of RXR␥-deficient mice. We found that RXR␥ is ex- pressed in developing cones in both the mouse and human retina and that RXR␥ is downregulated at the time of S-opsin From the 1Graduate Program in Neurobiology and Behavior and onset in both species. Like TR␤2-deficient mice, RXR␥-defi- the 2Department of Biological Structure, University of Washington, cient mice express S-opsin in every cone. Unlike TR␤2-defi- Seattle, Washington. cient mice, however, RXR␥-deficient mice have a normal M- Supported by National Institutes of Health Grants NS28308 (TAR) opsin gradient. Thus, RXR␥ is involved in the regulation of the and T32 EY07031 (MRR). expression of S-opsin expression, but not that of M-opsin, Submitted for publication January 25, 2005; revised March 28, which suggests that M- and S-opsin are independently regu- 2005; accepted March 31, 2005. lated by different nuclear hormone receptor complexes. Disclosure: M.R. Roberts, None; A. Hendrickson, None; C.R. McGuire, None; T.A. Reh, None The publication costs of this article were defrayed in part by page METHODS charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Animals Corresponding author: Thomas A. Reh, University of Washington, Department of Biological Structure, Box 357420, Seattle, WA 98195; RXR␥-null mice (C57BL/6; from Ronald Evans, The Salk Institute, La [email protected]. Jolla, CA)2 were genotyped with separate DNA primer pairs for the Investigative Ophthalmology & Visual Science, August 2005, Vol. 46, No. 8 Copyright © Association for Research in Vision and Ophthalmology 2897 Downloaded from iovs.arvojournals.org on 09/26/2021 2898 Roberts et al. IOVS, August 2005, Vol. 46, No. 8 wild-type (5Ј-ACTAGTGGATCCACTCCACTTCC-3Ј,5Ј-ACTGCGCTGG- or lowest S opsin expression was 0° dorsal. The average percentage of TGCGAATGATTGT-3Ј) and the RXR␥-null allele (5Ј GACACCAGAC- opsinϩ cones (ϮSEM) was reported for fields in the dorsal, central, and CAACTGGTAATGG-3Ј,5Ј-GCATCGAGCTGGGTAATAAGCG-3Ј). Reac- ventral thirds of each retina. Statistical significance was determined tions containing all four primers were amplified for 28 cycles (30 with a one-way ANOVA. seconds at 94°C, 1 minute at 60°C, and 1 minute at 72°C). The day of birth was designated postnatal day (P)0. Human fetal eyes were ob- RESULTS tained from the Human Embryology Laboratory (University of Wash- ington School of Medicine) or from ABR, Inc. (Alameda, CA). All RXR␥ in Mouse and Human Cones experiments were conducted in accordance with the institutional ␥ guidelines of the University of Washington School of Medicine and the Previous reports indicate that one of the RXR isoforms, RXR , ARVO Statement for the Use of Animals in Ophthalmic and Vision is expressed in both mature mouse cones and in putative cones 6,17 Research. of the developing mouse retina. We used both immunoflu- orescence and in situ hybridization to confirm these reports. Tissue Preparation We also used an immunofluorescence to assay for RXR␥ ex- pression in developing human cones. For immunohistochemistry, retinas were dissected in cold phosphate- In the embryonic mouse retinas, RXR␥ antibodies labeled buffered saline (PBS), fixed for 2 hours in 4% paraformaldehyde, rinsed nuclei in the developing ganglion cell layer and at the scleral in PBS, and equilibrated in 30% sucrose/PBS overnight at 4°C. Retinas surface (developing photoreceptor layer) as early as embryonic were frozen in optimal cutting temperature compound (OCT, Tissue- day (E)14.5. RXR␥ expression extended along the length of the ␮ Tek; Sakura Finetek, Torrance, CA) and cryosectioned at 12 m retina in these regions by E15.5 (Fig. 1A). In situ hybridization ␮ (mouse) or 20 m (human). for RXR␥ mRNA showed a pattern of expression similar to that observed with the antiserum (Fig. 1B). The scleral surface of Immunohistochemistry and Flatmounts the developing retina contains both dividing progenitor cells Slides were incubated overnight in primary antibodies—1:200 rabbit and immature photoreceptors. To test directly whether the RXR␥ (sc-555, lot A1111), 1:150 goat S-sensitive opsin (sc-14363; Santa cells that express RXR␥ are progenitors or immature photore- Cruz Biotechnology, Santa Cruz, CA), 1:500 rabbit S-opsin or M-opsin ceptors, we double-labeled retinal sections from E16 mice with (AB5407, AB5745; Chemicon International, Temecula, CA), 1:10,000 RXR␥ and an antibody to phosphohistone H3, which is ex- rabbit TR␤2 (a gift from Lily Ng and Douglas Forrest), or 1:200 rat pressed specifically in mitotic progenitors (Fig. 1C). We did not monoclonal phosphohistone H3 (Ab10543; Novus Biologicals, Little- find any phosphohistone-expressing cells at the scleral surface ton, CO)—and for 2 hours in secondary antibodies (1:500 AlexaFluor of E16 retinas that also expressed RXR␥, indicating that RXR␥ goat anti-rabbit 568, goat anti-rat 488, donkey anti-rabbit 568, or is not expressed in progenitors. Thus, the RXR␥-positive cells chicken anti-goat 488; Molecular Probes, Inc., Eugene, OR).
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