Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina.

Most mammals have two types of cone photoreceptors, which contain either medium wavelength (M) or short wavelength (S) opsin. The number and spatial organization of cone types varies dramatically among species, presumably to fine-tune the retina for different visual environments. In the mouse, S- and M-opsin are expressed in an opposing dorsal-ventral gradient. We previously reported that cone opsin patterning requires thyroid hormone beta2, a nuclear hormone receptor that regulates transcription in conjunction with its ligand, thyroid hormone (TH). Here we show that exogenous TH inhibits S-opsin expression, but activates M-opsin expression. Binding of endogenous TH to TRbeta2 is required to inhibit S-opsin and to activate M-opsin. TH is symmetrically distributed in the retina at birth as S-opsin expression begins, but becomes elevated in the dorsal retina at the time of M-opsin onset (postnatal day 10). Our results show that TH is a critical regulator of both S-opsin and M-opsin, and suggest that a TH gradient may play a role in establishing the gradient of M-opsin. These results also suggest that the ratio and patterning of cone types may be determined by TH availability during retinal development.

Retinoid X receptor (gamma) is necessary to establish the S-opsin gradient in cone photoreceptors of the developing mouse retina.

PURPOSE: The retinoid X receptors (RXRs) are members of the family of ligand-dependent nuclear hormone receptors. One of these genes, RXRgamma, is expressed in highly restricted regions of the developing central nervous system (CNS), including the retina. Although previous studies have localized RXRgamma to developing cone photoreceptors in several species, its function in these cells is unknown. A prior study showed that thyroid hormone receptor beta2 (TRbeta2) 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 RXRgamma cooperates with TRbeta2 to regulate cone opsin patterning, the developmental expression of RXRgamma was examined, and cone opsin expression in RXRgamma-null mice was analyzed. RESULTS: RXRgamma was expressed in postmitotic cones and was transiently downregulated at the time of S-opsin onset in both mouse and human cones. RXRgamma-null mice expressed S-opsin in all cones, similar to the TRbeta2-null mice. Unlike TRbeta2-null mice, which did not express M-opsin, RXRgamma-null mice had a normal pattern of M-opsin expression. CONCLUSIONS: RXRgamma is essential (along with TRbeta2) 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.