Developmental Changes of Cone Opsin Expression but Not Retinal Morphology in the Hypothyroid Pax8 Knockout Mouse

Glaschke, Anika; Glösmann, Martin; Peichl, Leo

doi:10.1167/iovs.09-3592

Cited by 39 publications

(46 citation statements)

References 44 publications

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“…Although TH signaling plays a major role in cone opsin expression and patterning and high TH signaling induces cone and rod death, suppressing TH signaling has no negative effect on cone and rod structure, function (as evaluated by electroretinogram analysis), or survival during development and in adult mice (7,30,31). This is in agreement with the observations in a human patient carrying TRβ2 mutations.…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…Eyes were fixed in 4% paraformaldehyde/0.1 M phosphate buffer. Retinas were dissected and blocked, and cone opsins were detected using polyclonal rabbit anti-M-opsin (JH492) (Wang et al, 1992) and polyclonal goat anti-S-opsin (sc-14363; Santa Cruz Biotechnology) as described previously (Glösmann et al, 2008;Glaschke et al, 2010). Sampling of retinal regions for comparison of cone opsin patterns between experimental and control animals followed that of Glaschke et al (2010).…”

Section: Control Pax8mentioning

confidence: 99%

“…Retinas were dissected and blocked, and cone opsins were detected using polyclonal rabbit anti-M-opsin (JH492) (Wang et al, 1992) and polyclonal goat anti-S-opsin (sc-14363; Santa Cruz Biotechnology) as described previously (Glösmann et al, 2008;Glaschke et al, 2010). Sampling of retinal regions for comparison of cone opsin patterns between experimental and control animals followed that of Glaschke et al (2010). Polyclonal rabbit anti-mouse active caspase 3 (AF835; R&D Systems) and monoclonal rabbit anti-Ki67 (clone SP6; RM-9106; Thermo Fisher Scientific) were used to identify apoptotic and proliferating cells, respectively, in frozen sections of adult retina.…”

Section: Control Pax8mentioning

confidence: 99%

“…The spectral identity and the retinal distribution of S-and M-cones, once specified, are thought to be rigidly preserved to support visual functions such as contrast and color vision. 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%

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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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“…Loss of EcR function and a subsequent decline in sensitivity to ecdysone prevents larval photoreceptors from switching to Rh6 expression (Sprecher and Desplan, 2008). In mouse, opsin switching is believed to occur during cone development (Glaschke et al, 2010) and thyroid hormone levels are crucial for both cone maturation and the establishment of the opsin retinal gradient in this animal (Roberts et al, 2006;Lu et al, 2009;Ng et al, 2010).…”

Section: Thyroid Hormone Is Necessary For Uv-to-blue Opsin Switching mentioning

confidence: 99%

Thyroid hormone accelerates opsin expression during early photoreceptor differentiation and induces opsin switching in differentiated TRα‐expressing cones of the salmonid retina

Gan

Flamarique

2010

Developmental Dynamics

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Thyroid hormone and its receptors (TRs) regulate photoreceptor differentiation and visual pigment protein (opsin) expression in the retinas of several vertebrates, including rodents and fish. In some of these animals, opsin expression can arise through switches within differentiated cone photoreceptors. In salmonid fishes, single cones express ultraviolet (SWS1) opsin during embryonic development and switch to blue (SWS2) opsin as the fishes grow. It is unknown whether thyroid hormone regulates opsin expression during early cone differentiation and acts through TRs to induce opsin switches in differentiated cones of the salmonid retina. Using in situ hybridization, we characterized the spatiotemporal dynamics of opsin expression and switching in embryos treated with exogenous thyroid hormone or propylthiouracil (PTU), a pharmacological inhibitor of thyroid hormone synthesis. We combined immunohistochemistry with in situ hybridization to map TRa expression with respect to cones undergoing the opsin switch in older juvenile fish. Thyroid hormone accelerated opsin expression in differentiating cones and induced the opsin switch in differentiated single cones, whereas PTU repressed the opsin switch. TRa was not detected in differentiating photoreceptors as opsin expression initiated, but was later expressed in differentiated single cones before the onset of the opsin switch. TRa expression exhibited a dynamic dorsoventral distribution that paralleled the progression of the opsin switch. Together, our results show that thyroid hormone is required for opsin switching in the retina of salmonid fishes and suggest that TRa may be involved in regulating this phenomenon. Developmental Dynamics 239:2700-2713,

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Developmental Changes of Cone Opsin Expression but Not Retinal Morphology in the Hypothyroid Pax8 Knockout Mouse

Cited by 39 publications

References 44 publications

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

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

Thyroid hormone accelerates opsin expression during early photoreceptor differentiation and induces opsin switching in differentiated TRα‐expressing cones of the salmonid retina

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