Type 3 Deiodinase, a Thyroid-Hormone-Inactivating Enzyme, Controls Survival and Maturation of Cone Photoreceptors

Abstract

Maturation of the mammalian nervous system requires adequate provision of thyroid hormone and mechanisms that enhance tissue responses to the hormone. Here, we report that the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase, a thyroid hormone-inactivating enzyme. Type 3 deiodinase, encoded by Dio3, is expressed in the immature mouse retina. In Dio3 −/− mice, ~80% of cones are lost through neonatal cell death. Cones that express opsin photopigments for response to both short (S) and medium-long (M) wavelength light are lost. Rod photoreceptors, which mediate dim light vision, remain largely intact. Excessive thyroid hormone in wild type pups also eliminates cones. Cone loss is mediated by cone-specific thyroid hormone receptor β2 (TRβ2) as deletion of TRβ2 rescues cones in Dio3 −/− mice. However, rescued cones respond to short but not longer wavelength light because TRβ2 under moderate hormonal stimulation normally induces M opsin and controls the patterning of M and S opsins over the retina. The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function.

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

“…T3-induced cone death did not occur in Thrβ2 −/− mice, and cone degeneration caused by deficiency of type 3 iodothyronine deiodinase (DIO3, an enzyme that inactivates T3) was rescued in Dio3 −/− /Thrβ2 −/− mice (12). It would be interesting to develop a Rpe65 −/− /Thrβ2 −/− or a cpfl1/Thrβ2 −/− double knockout mouse model to investigate whether TRβ2 is involved in the survival of cones following TH signaling suppression.…”

“…Importantly, TH signaling has been associated with cone viability. Triiodothyronine (T3) treatment was shown to cause cone death in mice and this effect was reversed by deletion of TRβ2 gene (12). Excessive TH signaling was also shown to induce auditory defects and cochlear degeneration in mice (13).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…This is also observed in animal models of transgenic Dio2 expression in the heart (273,274). In contrast, D3 inactivation results in localized increase in thyroid hormone signaling as evidenced in the D3 KO mouse (64,239,(275)(276)(277)(278)(279).…”

“…The dorso-ventral axis of the globe is marked. In situ hybridization and immunohistochemistry are used to assess expression of candidate target genes and are typically performed on 10-16 lm paraformaldehyde-fixed cryosections (279,398,503,504). Protein expression analyses can be performed on protein extracts prepared from dissected retina to investigate various opsin and rhodopsin proteins using Western blot and immunohistochemical studies (279,398,503,504,506).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Either excessive thyroid hormone given to wild-type pups or the elimination of D3 by gene targeting abolishes approximately 80% of the cones (mostly those expressing opsin photopigments) while the rod photoreceptors are spared. Type 3 deiodinase thus limits the exposure of the cones to T3, permitting both cone survival and the patterning of opsin that is required for cone function (43).…”