Developmental expression of thyroid hormone receptor β2 protein in cone photoreceptors in the mouse

Ng, Lily; Ma, Michelle; Curran, Tom; Forrest, Douglas

doi:10.1097/wnr.0b013e32832a2c63

Cited by 60 publications

(69 citation statements)

References 22 publications

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“…Several previous studies have demonstrated TR expression in the vertebrate retina (Sjöberg et al, 1992;Harpavat and Cepko, 2003;Mader and Cameron, 2006;Applebury et al, 2007;Ng et al, 2009;Raine and Hawryshyn, 2009). Both TRa and TRb are expressed in the retina of another fish, the winter flounder (Pleuronectes americanus), in addition to rainbow trout (Mader and Cameron, 2006;Raine and Hawryshyn, 2009).…”

Section: Discussionmentioning

confidence: 99%

Systemic thyroid hormone is necessary and sufficient to induce ultraviolet-sensitive cone loss in the juvenile rainbow trout retina

Raine

Coffin

Hawryshyn

2010

Journal of Experimental Biology

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SUMMARYRainbow trout possess ultraviolet-sensitive (UVS) cones in their retina that degenerate naturally during development. This phenomenon can be induced with exogenous thyroxine [T4, a thyroid hormone (TH)] treatment. However, the previous T4 exposure experiments employed static water immersion; a method that could introduce confounding stress effects on the fish. Because of this, it was uncertain if T4 alone was sufficient to induce retinal changes or if stress-related hormones were also necessary to initiate this process. Furthermore, it was unclear whether endogenous T4 was the factor responsible for initiating natural UVS cone loss during development. The current study examined the role of systemic T4 on the juvenile rainbow trout retina using a slow-release implant. Exogenous T4 treatment resulted in SWS1 opsin downregulation and UVS cone loss after four weeks of exposure, signifying that T4 is sufficient to induce this process. Blocking endogenous T4 production with propylthiouracil (PTU, an anti-thyroid agent) attenuated SWS1 downregulation and UVS cone loss in the retina of naturally developing rainbow trout, suggesting that endogenous T4 is necessary to initiate retinal remodelling during development. Quantitative real-time RT-PCR analysis demonstrated that several TH-regulating components are expressed in the trout retina, and that expression levels of the TH receptor isoform TRb and the type 2 deiodinase (D2) change with T4 treatment. This suggests that T4 may act directly on the retina to induce UVS cone loss. Taken together, these results demonstrate that systemic TH is necessary and sufficient to induce SWS1 opsin downregulation and UVS cone loss in the retina of juvenile rainbow trout.

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Section: Discussionmentioning

confidence: 99%

Systemic thyroid hormone is necessary and sufficient to induce ultraviolet-sensitive cone loss in the juvenile rainbow trout retina

Raine

Coffin

Hawryshyn

2010

Journal of Experimental Biology

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“…TH signaling regulating cone viability is likely mediated via TRβ2, which, in the retina, is expressed only in cones (33,34). 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).…”

Section: Discussionmentioning

confidence: 99%

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

Thapa

Morris

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunitdeficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotidegated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.R od and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as retinitis pigmentosa, macular degeneration, and cone-rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders (www.sph. uth.tmc.edu/RetNet/disease.htm), including those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65), and lecithin retinol acyltransferase (LRAT), and the phototransductionassociated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and cyclic nucleotidegated channel). There are currently no treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including oxidative damage (1, 2), endoplasmic reticulum stress (3, 4), and apoptosis (5, 6).Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in retina regarding its regulation of cone opsin expression and patterning has been well documented (7,8). Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long ...

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“…Alternatively, similar to S-opsin mRNA, TR␤2 expression may be topographically rearranged in a manner leaving total retinal transcript level(s) of TR␤2 unaltered. It is not yet established whether during early development cone-specific expression of TR␤2 is dorsoventrally graded (Fujieda et al, 2009) or not (Roberts et al, 2005;Applebury et al, 2007), and available methodology appears to lack sufficient sensitivity to resolve the spatiotemporal characteristics of Tr␤2 expression in the adult retina with cellular precision (Applebury et al, 2007;Ng et al, 2009) (our own attempts with riboprobes), likely because of low TR␤2 levels present. Future efforts therefore should evaluate TR␤2 expression in the wild-type compared with the hypothyroid adult retina.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse early postnatal development, thyroid hormone (TH), through its receptor TR␤2, is an important regulator of cone spectral identity by repressing S-opsin and activating M-opsin (Ng et al, 2001;Roberts et al, 2006;Applebury et al, 2007;Pessô a et al, 2008;Lu et al, 2009, Glaschke et al, 2010. In the adult retina, however, the role of TH signaling in opsin regulation is unclear, despite an abundance of hormone (Ientile et al, 1984;Roberts et al, 2006) and the persistent, albeit low expression of TR␤2 in cones (Applebury et al, 2007;Fujieda et al, 2009;Ng et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Controls Cone Opsin Expression in the Retina of Adult Rodents

Glaschke¹,

Weiland²,

Turco³

et al. 2011

J. Neurosci.

103

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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 TR␤2, 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 Ϫ/Ϫ 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.

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Developmental expression of thyroid hormone receptor β2 protein in cone photoreceptors in the mouse

Cited by 60 publications

References 22 publications

Systemic thyroid hormone is necessary and sufficient to induce ultraviolet-sensitive cone loss in the juvenile rainbow trout retina

Systemic thyroid hormone is necessary and sufficient to induce ultraviolet-sensitive cone loss in the juvenile rainbow trout retina

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

Thyroid Hormone Controls Cone Opsin Expression in the Retina of Adult Rodents

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