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Is Necessary to Establish the S-opsin Gradient in Cone Photoreceptors of the Developing Mouse Retina
1From the Graduate Program in Neurobiology and Behavior and the 2Department of Biological Structure, University of Washington, Seattle, Washington.
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, is expressed in highly restricted regions of the developing central nervous system (CNS), including the retina. Although previous studies have localized RXR to developing cone photoreceptors in several species, its function in these cells is unknown. A prior study showed that thyroid hormone receptor ß2 (TRß2) is necessary to establish proper cone patterning in mice by activating medium-wavelength (M) cone opsin and suppressing short-wavelength (S) cone opsin. Thyroid hormone receptors often regulate gene transcription as heterodimeric complexes with RXRs.
METHODS. To determine whether RXR cooperates with TRß2 to regulate cone opsin patterning, the developmental expression of RXR was examined, and cone opsin expression in RXR-null mice was analyzed.
RESULTS. RXR was expressed in postmitotic cones and was transiently downregulated at the time of S-opsin onset in both mouse and human cones. RXR-null mice expressed S-opsin in all cones, similar to the TRß2-null mice. Unlike TRß2-null mice, which did not express M-opsin, RXR-null mice had a normal pattern of M-opsin expression.
CONCLUSIONS. RXR is essential (along with TRß2) for suppressing S-opsin in all immature cones and in dorsal cones in the mature retina, but it is not necessary for M-opsin regulation. These results demonstrate a critical role for RXRs in regulating cell differentiation in the CNS and highlight a remarkable conservation of opsin regulation from Drosophila to mammals.
, ß, and —have demonstrated that RXRs regulate several developmental processes, including cardiogenesis and neurogenesis.2 3 Although these studies have revealed some redundancy of function, they also have demonstrated some isoform-specific functions. For example, RXR heterodimerizes with retinoic acid receptors (RARs) to regulate retinal growth and cardiac development.4
Although all three isoforms are expressed in the developing nervous system, RXR has the most restricted and developmentally regulated expression. It is expressed in the developing striatum, part of the tegmentum, the pituitary, the ventral horns of the spinal cord,3 5 and the retina.6 RXR-null mice show isoform-specific defects in both striatal and hippocampal function, although RXRß can partially compensate for the loss of RXR in the striatum.2 7 8 RXR has also been identified in the developing retina of Xenopus, chicks, and mice.6 9 10 It has a highly restricted pattern of expression; and, in both chicks and mice, RXR is expressed in developing cones. Despite the conserved expression pattern in developing cone photoreceptors, the function of RXR in cone development is not known.
We have shown that thyroid hormone receptor ß2 (TRß2), another member of the same family of nuclear hormone receptors, has a role in the developmental "choice" of which opsin gene to express.11 Like most mammals, mice have two opsin proteins that respond maximally to different wavelengths: S-opsin to short wavelengths and M-opsin to longer wavelengths. However, the ratio and distribution of cone opsins varies dramatically among species (for review, see Ref. 12 ). For example, S-opsin is excluded from the central fovea of human retinas.13 14 In mice, however, there is an opposing gradient of M- and S-opsin, so that M-opsin expression is highest in dorsal cones, whereas S-opsin predominates in the ventral retina.15 TRß2-null mice show a profound disruption in the cone opsin gradient. In these mice, M-opsin is not expressed in any cones, indicating that TRß2 is necessary to upregulate M-opsin. In addition, all cones in TRß2-null mice express S-opsin, which indicates that TRß2 is also necessary to suppress S-opsin. Because TRs often regulate transcription as heterodimers with RXRs, we hypothesized that RXR may also play a part in the determination of cone opsin expression.
To determine whether RXR is necessary for proper cone photoreceptor development, we examined the expression of RXR during retinal development and analyzed the cone phenotype of RXR-deficient mice. We found that RXR is expressed in developing cones in both the mouse and human retina and that RXR is downregulated at the time of S-opsin onset in both species. Like TRß2-deficient mice, RXR-deficient mice express S-opsin in every cone. Unlike TRß2-deficient mice, however, RXR-deficient mice have a normal M-opsin gradient. Thus, RXR is involved in the regulation of the expression of S-opsin expression, but not that of M-opsin, which suggests that M- and S-opsin are independently regulated by different nuclear hormone receptor complexes.
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-null mice (C57BL/6; from Ronald Evans, The Salk Institute, La Jolla, CA)2 were genotyped with separate DNA primer pairs for the wild-type (5'-ACTAGTGGATCCACTCCACTTCC-3', 5'-ACTGCGCTGGTGCGAATGATTGT-3') and the RXR-null allele (5' GACACCAGACCAACTGGTAATGG-3', 5'-GCATCGAGCTGGGTAATAAGCG-3'). Reactions containing all four primers were amplified for 28 cycles (30 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 obtained from the Human Embryology Laboratory (University of Washington School of Medicine) or from ABR, Inc. (Alameda, CA). All experiments were conducted in accordance with the institutional guidelines of the University of Washington School of Medicine and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Tissue Preparation
For immunohistochemistry, retinas were dissected in cold phosphate-buffered saline (PBS), fixed for 2 hours in 4% paraformaldehyde, rinsed in PBS, and equilibrated in 30% sucrose/PBS overnight at 4°C. Retinas were frozen in optimal cutting temperature compound (OCT, Tissue-Tek; Sakura Finetek, Torrance, CA) and cryosectioned at 12 µm (mouse) or 20 µm (human).
Immunohistochemistry and Flatmounts
Slides were incubated overnight in primary antibodies—1:200 rabbit RXR (sc-555, lot A1111), 1:150 goat S-sensitive opsin (sc-14363; Santa Cruz Biotechnology, Santa Cruz, CA), 1:500 rabbit S-opsin or M-opsin (AB5407, AB5745; Chemicon International, Temecula, CA), 1:10,000 rabbit TRß2 (a gift from Lily Ng and Douglas Forrest), or 1:200 rat monoclonal phosphohistone H3 (Ab10543; Novus Biologicals, Littleton, CO)—and for 2 hours in secondary antibodies (1:500 AlexaFluor goat anti-rabbit 568, goat anti-rat 488, donkey anti-rabbit 568, or chicken anti-goat 488; Molecular Probes, Inc., Eugene, OR). To visualize cone outer segments, we incubated sections with FITC-conjugated peanut lectin (Sigma-Aldrich) for 2 hours. Sections were rinsed thoroughly in PBS before they were coverslipped (Fluoromount-G; Southern Biotechnology, Birmingham, AL). Slides were viewed on a confocal microscope (Axioplan 2 or LSM5 Pascal; Carl Zeiss Meditec, Dublin, CA), and photographed with a digital camera (Spot 2.3.1; Diagnostic Instruments, Sterling Heights, MI).
For flatmount studies, retinas were marked on the dorsal side with tissue-marking dye (Cancer Diagnostics, Inc., Birmingham, MI), flattened on a glass slide, fixed with 4% paraformaldehyde for 15 minutes, and fixed for an additional hour in a 24-well plate. Retinas were incubated in primary antibodies at the concentrations noted earlier for 48 hours at 4°C and in secondary antibodies overnight at 4°C. To label all cones, we incubated retinas in FITC-conjugated peanut lectin for 2 hours (PNA; Sigma-Aldrich). Retinas were mounted (Fluoromount-G; Southern Biotechnology) between coverslips separated by an imaging chamber (Secure-Seal; Grace Bio-Laboratories, Bend, OR).
In Situ Hybridization
Riboprobes were made to the full 1.6-Mb RXR transcript (Ronald Evans, The Salk Institute). Tissue preparation and riboprobe synthesis was described previously.16
Quantitative PCR
We prepared cDNA from wild-type and RXR-null retinas. Levels of RXR and -ß in P5 retinas and of M-opsin in adult retinas were measured by quantitative PCR, as described elsewhere.16 We analyzed three to five individuals of each genotype and age. Primer sequences are available on request.
Data Analysis
To determine the percentage of opsin+ cones in flatmounts, we counted the total number of PNA+ and opsin+ cones for at least sixteen 1.16-mm2 fields in four to five retinas for each genotype. The field within the dye-labeled dorsal quadrant with the highest M opsin or lowest S opsin expression was 0° dorsal. The average percentage of opsin+ cones (±SEM) was reported for fields in the dorsal, central, and ventral thirds of each retina. Statistical significance was determined with a one-way ANOVA.
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in Mouse and Human Cones, is expressed in both mature mouse cones and in putative cones of the developing mouse retina.6 17 We used both immunofluorescence and in situ hybridization to confirm these reports. We also used an immunofluorescence to assay for RXR expression in developing human cones.
In the embryonic mouse retinas, RXR antibodies labeled nuclei in the developing ganglion cell layer and at the scleral surface (developing photoreceptor layer) as early as embryonic day (E)14.5. RXR expression extended along the length of the retina in these regions by E15.5 (Fig. 1A) . In situ hybridization for RXR mRNA showed a pattern of expression similar to that observed with the antiserum (Fig. 1B) . The scleral surface of the developing retina contains both dividing progenitor cells and immature photoreceptors. To test directly whether the cells that express RXR are progenitors or immature photoreceptors, we double-labeled retinal sections from E16 mice with RXR and an antibody to phosphohistone H3, which is expressed specifically in mitotic progenitors (Fig. 1C) . We did not find any phosphohistone-expressing cells at the scleral surface of E16 retinas that also expressed RXR, indicating that RXR is not expressed in progenitors. Thus, the RXR-positive cells were most likely immature photoreceptors.
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, many of the RXR-expressing photoreceptors must be cones. Second, as the photoreceptors matured, we were able to confirm that RXR is expressed specifically in cone nuclei by double-labeling with peanut lectin, which binds specifically to cone outer segments, and with cone-specific opsins (described later). Every lectin-positive cone had an RXR-positive nucleus (Fig. 1D) and RXR was not present in rod nuclei (not shown).
We also analyzed the expression of RXR in human retinas, where it is much easier to distinguish immature cones from rods because of differences in their morphology and protein expression. An early marker of cone photoreceptors in human retina, tubby-like protein 1 (TULP-1), is expressed in cones before the onset of cone opsin expression.19 By double-label immunofluorescence, we found that all TULP-expressing cones had RXR-positive nuclei by fetal week (FW)16 (Fig. 2A) . -Transducin is another cone-specific marker that labels both S- and M-opsin-expressing cones in fetal human retina.20 At FW16, -transducin was visible in the cytoplasm of cones across much of the retina. These -transducin expressing cones also have RXR nuclei (Fig. 2B) . Thus, our data suggest that RXR is an early cone-specific marker.
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during Cone Development expression, we labeled mouse retinal sections from animals at ages E12.5 through adult. We found RXR expression in a few newly generated cones at the scleral surface and also in the ganglion cell layer beginning at E14.5 (Fig. 3A) . By E15.5, RXR was expressed uniformly across the retina (Fig. 1A) and remained robust until E17.5 (Fig. 3B) . However, there was a dramatic decline of RXR expression in cones just before birth. From E19 (Fig. 3C) to P2 (Fig. 3D) , we observed only small patches of isolated RXR-positive cones. We could not detect a consistent spatial pattern in the downregulation of RXR, and the patches of RXR varied in number and location, even between littermates. The downregulation in RXR was transient. By P5 all cones re-expressed RXR (Fig. 3E) . RXR expression persisted in cones through adult stages, though the intensity of expression was somewhat reduced after the first postnatal week (Fig. 3F) .
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in cones correlated with the onset of S-opsin expression, which begins at E18. We hypothesized that downregulation of RXR is necessary to allow induction of S-opsin. To determine whether the expression of these genes is consistent with the hypothesis, we labeled retinal sections with both S-opsin and RXR antisera at E19 (Figs. 3G 3H 3I) . Although we occasionally observed cells that expressed both S-opsin and RXR at this age, nearly all of the cones expressed either RXR or S-opsin, but not both. Most S-opsin-expressing cones were found in regions where RXR had been downregulated. Moreover, cones expressing the highest levels of S-opsin were usually RXR– or expressed very low levels of RXR. This downregulation was transient; by P5, RXR was re-expressed in all S-opsin-expressing cones (Figs. 3J 3K 3L) . The double-labeling results in mouse retina are consistent with the hypothesis that a transient downregulation of RXR in perinatal cones promotes the onset of S-opsin.
In human retinas, we also observed a transient downregulation of RXR in S-opsin-expressing cones at the time of S-opsin onset. At the beginning of S-opsin expression at FW14 and FW16 (Fig. 4) , the S-cones had undetectable or low levels of RXR. However, by FW18, when S-opsin expression has reached the edge of the retina,13 most S-opsin-expressing cones also re-expressed RXR (not shown).
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and TRß2 during Cone Maturation, we labeled retinal sections and flatmounts with TRß2 antiserum, which was raised against an N-terminal polypeptide of mouse TRß2 (Lily Ng, Iwan Jones, and Douglas Forrest). We observed TRß2 in postmitotic cones at E14.5, corresponding with the time of RXR onset (data not shown). By E15.5, TRß2 and RXR were uniformly expressed in developing cones (Fig. 5A , compare with RXR in Fig. 1A ). However, between E19 and P2, we observed a downregulation of TRß2 in cones, similar to that described for RXR (Fig. 5B) . At P5, TRß2 was re-expressed in S-opsin-positive cones (Figs. 5C 5D) . TRß2 expression declined after the first postnatal week and was present at very low levels in adult cones (not shown).
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-Deficient Mice has a role in the regulation of cone opsin expression, we analyzed RXR-null mice for changes in opsin expression. TRß2-null mice do not express M-opsin, but all cones express S-opsin.11 Because RXR heterodimerizes with TRß2 and both receptors are expressed in developing cone nuclei, we hypothesized that RXR is necessary, along with TRß2, to regulate cone opsin expression and predicted that RXR-null mice would have a phenotype similar to that of TRß2-null mice.
In wild-type mice, the S-opsin-expressing cones were concentrated in the ventral retina, and there were few S-opsin-positive cones in the most dorsal retina. This gradient is established during development. Even in P0 retinas, many more ventral cones than dorsal cones expressed S-opsin (Figs. 6A 6C) . By contrast, P0 RXR-null mice had a profound disruption in the normal pattern of S-opsin expression: S-opsin was expressed at nearly equal levels in both dorsal and ventral cones (Figs. 6B 6D) . The ectopic expression of S-opsin was maintained in RXR-null adult retinas. In adult RXR-null retinas, nearly all cones expressed S-opsin (Figs. 6F 6H) , whereas in wild-type retinas, few dorsal cones expressed S-opsin (Figs. 6E 6G) . This phenotype was similar to that of TRß2-null mice, and supports our hypothesis that a TRß2-RXR heterodimer is necessary to establish the S-opsin gradient by suppressing its expression in a subset of dorsal cones.
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-null mice for changes in M-opsin expression. Remarkably, we did not find the same M-opsin phenotype in RXR-null retinas that we had in TRß2-null retinas. M-opsin expression in RXR-null retinal sections (Figs. 6J 6L) was indistinguishable from the gradient in wild-type sections (Fig. 6I 6K) . We also used quantitative PCR to confirm that the level of M-opsin expression is similar between wild-type and RXR-null retinas (data not shown).
To quantify the opsin gradients in wild-type, RXR+/–, and RXR-null retinas, we coimmunolabeled retinal flatmounts with an opsin antibody and FITC-peanut lectin (PNA), which labeled all cones (Figs. 7A 7B 7C 7D) . We determined the percentage of cones that expressed S-opsin in the dorsal, central, and ventral regions of the retina (Fig. 7E) . In wild-type retinas, 19% of dorsal cones, 63% of central cones, and 86% of ventral cones expressed S-opsin. By contrast, almost all cones in RXR-null retinas expressed S-opsin; 93%, 98%, and 96% of cones expressed S-opsin in the dorsal, central, and ventral retina, respectively. We found a significant gene-dosage effect of RXR inactivation on the S-opsin gradient. In RXR+/– animals, S-opsin was expressed in 40% of dorsal, 86% of central, and 92% of ventral cones. Counts of M-opsin-expressing cones showed that 94%, 79%, and 34% of wild-type cones expressed M-opsin, compared with 88%, 63%, and 34% of RXR-null cones in the dorsal, central, and ventral retinas, respectively (Fig. 7E) .
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and RXRß are also expressed in the retina6 and have been shown to compensate for RXR function in other systems.7 To determine whether other RXR isoforms are upregulated in RXR-null retinas, we performed quantitative PCR to compare the levels of RXR and -ß in wild-type and RXR-null retinas at P5. RXR expression was not affected in RXR-null retinas. We found a small increase (3.6-fold) of RXRß in RXR-null retinas. However, because of high variation between animals, this increase was not significantly significant. To examine further whether RXRß compensates for RXR in M-opsin regulation, we counted the number of M-opsin-expressing cones in RXRß/ double-null mice. M-opsin expression in RXRß/ double-retinas was still graded, but M-opsin expression was significantly reduced compared to RXR-null retinas (data not shown).
Taken together, our results indicate that both RXR and TRß2 are necessary to establish the ventral–dorsal gradient of S-opsin by suppressing its expression in a subset of dorsal cones. However, there is a need for TRß2, but not for RXR, in the regulation of M-opsin expression. Thus, the expression of M- and S-opsin in developing cone photoreceptors is regulated by different nuclear receptor complexes.
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in cone photoreceptors of several species.6 9 10 To determine whether RXR has a role in cone development, we examined its spatial and temporal expression and the effect of RXR loss of function on opsin expression in the mouse retina. We found that RXR is necessary for the developmental determination of cone opsin expression. Mice deficient in RXR express S-opsin in nearly every cone, resulting in a loss of normal cone opsin patterning. Although we confirmed the previous reports that RXR is expressed in developing and adult cone photoreceptors, we found a striking, but transient, downregulation of RXR and TRß2 in the perinatal retina that coincided with S-opsin onset. We also found that RXR was expressed in developing human cone photoreceptors, suggesting that the function of this gene in cone development is conserved.
We propose that RXR and TRß2 cooperate to regulate the pattern of S-opsin expression in developing cones. Studies in many systems have shown that TR/RXR heterodimers can regulate transcription.21 22 23 24 We have reported that mice deficient in TRß2 show a profound disruption in the normal pattern of opsin expression in cone photoreceptors.11 We now show that both TRß2 and RXR are present in developing cones and that loss of either receptor results in a similar disruption in the pattern of S-opsin expression. Thus, it is likely that heterodimers of RXR and TRß2 normally establish the pattern of S-opsin expression by inhibiting it in many of the dorsal retinal cones. Of interest, both RXR and TRß2 were transiently downregulated at S-opsin onset in both mice and humans, suggesting that this downregulation is necessary for the timing of S-opsin expression.
In contrast with our previous analysis of the TRß2-null mice, we found that RXR was not necessary for activation of M-opsin expression. Although TRß2-null cones do not express M opsin, RXR-null retinas have normal M-opsin expression. Thus, S- and M-opsin must be regulated by different nuclear receptor complexes. Because RXRß and - are also expressed in the retina,6 we hypothesized that one of these isoforms may dimerize with TRß2 and compensate for RXR’s loss, much as RXRß does in the striatum.7 However, we did not find an upregulation of either RXR or -ß in RXR-null retinas and found that M-opsin expression was graded but reduced in RXRß/-double-null retinas. We could not examine M-opsin in RXR-null mice because they die in utero.5 Thus, we cannot rule out that RXR alone is sufficient to compensate for the loss of both RXR and -ß without being significantly upregulated. Incomplete compensation by RXR could explain the small but significant decrease of M-opsin in the central retina of RXR-null mice.
Our model of how RXR fits into photoreceptor development is shown in Figure 8 . Cones are generated in mice from multipotent progenitors from E10.5 to E16.18 Shortly after withdrawal from the cell cycle, both rods and cones express photoreceptor-specific transcription factors such as crx and NeuroD1.25 Several nuclear hormone receptors are involved in regulating the next stages of photoreceptor differentiation. Nr2e3 is an orphan nuclear receptor that is expressed in rods.26 27 Mutations in Nr2e3 underlie the human enhanced S-syndrome, and mouse mutants in this gene have an increased number of S-cones.28 29 30 Targeted deletion of Nrl, a leucine zipper transcription factor upstream of Nr2e3, has an even more extreme phenotype. Rods fail to develop and nearly all photoreceptors become S-opsin-expressing cones.31 We have shown that TRß2 is critical for the developmental choice between S- and M-opsin in cones,11 and now we show that RXR is also a critical regulator of this step. In our model, RXR/TRß2 heterodimers suppress S-opsin expression in a subset of cones, whereas M-opsin is regulated by either a TRß2 homodimer or TRß2 with an unknown heterodimeric partner.
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or TRß2 expression in developing mouse retinas, it is unlikely that regulation of receptor expression alone controls the dorsal–ventral cone opsin gradient. Rather, we propose that a gradient in one or both of the ligands for these receptors controls cone opsin patterning. There is evidence of at least two ligands for RXRs: 9-cis retinoic acid and the polyunsaturated fatty acid docosahexanoic acid.32 33 Although several studies have described gradients in all-trans-retinoic acid,34 35 the ligand for RARs, the distribution of RXR ligands in the retina has not been reported. Nevertheless, there is evidence that ligand-dependent RXR activation occurs normally in the developing retina,9 consistent with the possibility that a gradient in an RXR ligand controls the graded pattern of opsin expression.
The transcriptional mechanisms that control photoreceptor specification are remarkably well conserved among species. Notably, the Drosophila homologue of RXR, ultraspiracle (usp), regulates opsin transcription in a heterodimeric complex with the ecdysone receptor, the fly homologue of thyroid hormone receptor. Flies have eight photoreceptors (R1–8) that express one of five opsins. The R7 photoreceptor expresses either Rh-3 or Rh-4 opsin (for review, see Ref. 36 ). Remarkably, R7 photoreceptors in usp-null flies express only Rh-3.37 38 Thus, usp may suppress Rh-3 in fly photoreceptors, just as RXR suppresses S-opsin in mice. Because the transcriptional machinery controlling opsin expression is well conserved, RXR, TRß2, and their ligands may be used to generate highly varying photoreceptor patterns in a multitude of species, from flies to humans.
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Acknowledgements |
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Submitted for publication January 25, 2005; revised March 28, 2005; accepted March 31, 2005.
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 charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Thomas A. Reh, University of Washington, Department of Biological Structure, Box 357420, Seattle, WA 98195; tomreh{at}u.washington.edu.
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). Scale bar, 10 µm.
