Thyroid Hormone Signaling and Cone Photoreceptor Viability

Abstract

Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression. TH signaling inhibits S opsin expression, stimulates M opsin expression, and promotes dorsal-ventral opsin patterning. TH signaling has also been associated with cone photoreceptor viability. Treatment with thyroid hormone triiodothyronine (T3) or induction of high T3 by deleting the hormone-inactivating enzyme type 3 iodothyronine deiodinase (DIO3) causes cone death in mice. This effect is reversed by deletion of the TH receptor (TR) gene. Consistent with the T3 treatment effect, suppressing TH signaling preserves cones in mouse models of retinal degeneration. The regulation of cone survival by TH signaling appears to be independent of its regulatory role in cone opsin expression. The mechanism by which TH signaling regulates cone viability remains to be identified. The current understanding of TH signaling regulation in photoreceptor viability suggests that suppressing TH signaling locally in the retina may represent a novel strategy for retinal degeneration management.

Evidence for an Association between Macular Degeneration and Thyroid Cancer in the Aged Population

“…A recent study showed that suppressing thyroid hormone signaling could preserve cone photoreceptors in animal models of macular degeneration [ 13 ]. By contrast, administration of high doses of the thyroid hormone triiodothyronine caused cone photoreceptor death in animal models, and deletion of the thyroid hormone receptor gene could reverse this effect [ 14 ]. In a prospective cohort study, Chaker et al discovered that higher free thyroxine levels were associated with an increased risk of AMD [ 15 ].…”

“…In a prospective cohort study, Chaker et al discovered that higher free thyroxine levels were associated with an increased risk of AMD [ 15 ]. These studies suggested that using levothyroxine, which is also employed in thyroid suppression therapy usually administered to thyroid cancer patients, would increase the risk of AMD [ 10 , 11 , 12 , 13 , 14 , 15 ].…”

Moderate perinatal thyroid hormone insufficiency alters visual system function in adult rats

“…In the retina, developmental hypothyroidism causes a reduction of retinal progenitor cells, reduced retinal thickness, altered photoreceptor patterning, improperly formed photoreceptor outer segments, and reduced cell density in the retinal ganglion cell layer (Navegantes et al, 1996, Ng et al, 2001, Sevilla-Romero et al, 2002, Harpavat and Cepko, 2003, Roberts et al, 2006, Ng et al, 2011, Pinazo-Duran et al, 2011, Ma and Ding, 2016. Post-mitotic retinal precursor cells differentiate into all types of photoreceptors including rods, middlewavelength sensitive (M, "green") cones, short-wavelength sensitive (S, "blue") cones.…”

Expression of the inactivating deiodinase, Deiodinase 3, in the pre-metamorphic tadpole retina

“…When TH deiodination is impaired by iopanoic acid treatment, T 3 treatment further enhances the deleterious eye phenotype, revealing a crucial role for thra as aporeceptor and pinpointing that TH availability is tightly controlled [ 4 ] during eye development. D3 plays an essential protective role in inhibiting TH-induced proliferation in CMZ, resulting in an asymmetric growth in Xenopus laevis retina during metamorphosis [ 13 , 11 ], or in protecting certain photoreceptors from excessive T 3 signaling in the mouse and zebrafish retina [ 5 , 12 , 14 ]. These findings favor the hypothesis of a control of local TH availability mostly by the inactivating deiodinase D3.…”

“…As to other species, the role of TH on retinal development has been addressed during embryogenesis in rodents [ 10 , 14 ], during pro-metamorphosis in fish [ 5 ] as well as during metamorphosis in Xenopus [ 4 , 11 ].…”