RESUMEN
Mammalian retinas display an astonishing diversity in the spatial arrangement of their spectral cone photoreceptors, probably in adaptation to different visual environments. Opsin expression patterns like the dorsoventral gradients of short-wave-sensitive (S) and middle- to long-wave-sensitive (M) cone opsin found in many species are established early in development and thought to be stable thereafter throughout life. In mouse early development, thyroid hormone (TH), through its receptor TRß2, is an important regulator of cone spectral identity. However, the role of TH in the maintenance of the mature cone photoreceptor pattern is unclear. We here show that TH also controls adult cone opsin expression. Methimazole-induced suppression of serum TH in adult mice and rats yielded no changes in cone numbers but reversibly altered cone patterns by activating the expression of S-cone opsin and repressing the expression of M-cone opsin. Furthermore, treatment of athyroid Pax8(-/-) mice with TH restored a wild-type pattern of cone opsin expression that reverted back to the mutant S-opsin-dominated pattern after termination of treatment. No evidence for cone death or the generation of new cones from retinal progenitors was found in retinas that shifted opsin expression patterns. Together, this suggests that opsin expression in terminally differentiated mammalian cones remains subject to control by TH, a finding that is in contradiction to previous work and challenges the current view that opsin identity in mature mammalian cones is fixed by permanent gene silencing.
Asunto(s)
Opsinas de los Conos/biosíntesis , Regulación de la Expresión Génica , Retina/metabolismo , Opsinas de Bastones/biosíntesis , Hormonas Tiroideas/fisiología , Factores de Edad , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Hipotiroidismo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factor de Transcripción PAX8 , Factores de Transcripción Paired Box/biosíntesis , Factores de Transcripción Paired Box/deficiencia , Factores de Transcripción Paired Box/genética , Ratas , Ratas Endogámicas BNRESUMEN
PURPOSE: The effects of postnatal hypothyroidism on retinal development and spatial patterning of cone opsin expression were studied in Pax8-deficient mice. Pax8(-/-) mice are incapable of synthesizing thyroxine and serve as a model for congenital hypothyroidism. METHODS: Pax8(-/-), Pax8(+/-), and Pax8(+/+) littermates were studied. Serum thyroid hormone levels, body weight, and eye size were measured. Retinal cell-type-specific antibodies were used on frozen sections to examine the postnatal development of the major retinal cell classes and of retinal structure. The expression of short-wavelength-sensitive (S) and middle-to-long-wavelength-sensitive (M) cone opsins was assessed with opsin antibodies on retinal sections and whole retinas. The pattern of S opsin mRNA was assessed by in situ hybridization. RESULTS: In Pax8(-/-) mice, S opsin was upregulated in all cones, whereas M opsin was downregulated throughout the retina, the wild-type dorsoventral gradients of S and M opsin expression were absent. Otherwise, Pax8(-/-) mice showed no overt mutant phenotype in eye size, gross retinal anatomy, and the time-course of structural differentiation of retinal photoreceptors, horizontal cells, bipolars, amacrines, ganglion cells, and Müller glia cells. CONCLUSIONS: Pax8(-/-) mice show a pattern of cone opsin expression that differs substantially from the wild-type pattern, but exhibit no apparent alterations in general retinal development. The finding that a postnatal decrease in serum thyroid hormone yields changes in postnatal cone opsin expression is consistent with a ligand-dependent role of thyroid hormone receptor beta2 in S opsin repression and M opsin activation.