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

Ma, Hongwei; Thapa, Arjun; Morris, Lilah F.; Redmond, T. Michael; Baehr, Wolfgang; Ding, Xi

doi:10.1073/pnas.1317041111

Cited by 57 publications

(84 citation statements)

References 38 publications

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“…It would be interesting to maintain the animals on T3 for longer periods to determine if longer treatment can result in complete reversal of S opsin gradient. However, high levels of T3 can also affect cone survival and overall affect the health of the animals (Ma et al, 2014). Nonetheless, our data demonstrates that T3 supplementation can partially reverse the cone opsin phenotype resulting from Bmal1 deletion.…”

Section: Resultsmentioning

confidence: 99%

The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function

et al. 2017

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SUMMARY Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to photoreceptor development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular function of circadian activity within cone photoreceptors and reveal a role for the clock genes Bmal1 and Per2 in regulating cone spectral identity. ChIP analysis revealed that BMAL1 binds to the promoter region of the thyroid hormone-activating enzyme type 2 iodothyronine deiodinase (Dio2) and thus regulates the expression of Dio2. Thyroid hormone treatment resulted in a partial rescue of the phenotype caused by the loss of Bmal1, thus revealing a functional relationship between Bmal1 and Dio2 in establishing cone photoreceptor identity. Furthermore, Bmal1 and Dio2 are required to maintain cone photoreceptor functional integrity. Overall, our results suggest a mechanism by which circadian proteins can locally regulate the availability of thyroid hormone and influence tissue development and function.

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Section: Resultsmentioning

confidence: 99%

The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function

et al. 2017

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“…Rpe65 -/-and cpfl1 mice show rapid and severe cone death. Suppressing TH signaling with anti-thyroid drugs significantly improved cone survival in these mice (Ma et al 2014). It is worth mentioning that anti-thyroid treatment does not cause rod degeneration, although T3 treatment or deletion of DIO3 has been shown to reduce rod numbers (Ng et al 2010;Ma et al 2014).…”

Section: Dio3mentioning

confidence: 94%

“…Studies using Cngb3 −/− and Gucy2e −/− mice, models of retinal degeneration, also demonstrated that stimulating TH signaling by T3 treatment deteriorates cones (Ma et al 2014).…”

Section: Dio3mentioning

confidence: 96%

“…Stimulating TH signaling in Cngb3 -/-and Gucy2e -/-mice increased cone death, which was accompanied by reduced levels of S-opsin expression (Ma et al 2014). Stimulating TH signaling induces degeneration of rods (Ng et al 2010;Ma et al 2014) and cochlear hair cells (Ng et al 2009b), which do not express cone opsin. Moreover, TH signaling induces death in numerous cancer cell lines (Yamada-Okabe et al 2003;Chiloeches et al 2008;Sar et al 2011).…”

Section: Dio3mentioning

confidence: 99%

“…Suppressing TH signaling in Rpe65 -/-and cpfl1 mice greatly reduced cone death, which was accompanied by increased expression of S-opsin, increased S cones, and decreased M cones (Ma et al 2014). Stimulating TH signaling in Cngb3 -/-and Gucy2e -/-mice increased cone death, which was accompanied by reduced levels of S-opsin expression (Ma et al 2014).…”

Section: Dio3mentioning

confidence: 99%

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Thyroid Hormone Signaling and Cone Photoreceptor Viability

Ding

2015

Advances in Experimental Medicine and Biology

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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.

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Hypothalamus‐Pituitary‐Thyroid Axis

Ortiga-Carvalho

Chiamolera

Pazos‐Moura

et al. 2016

Comprehensive Physiology

336

222

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The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. Other neural, humoral, and local factors modulate the HPT axis and, in specific situations, determine alterations in the physiological function of the axis. The roles of THs are vital to nervous system development, linear growth, energetic metabolism, and thermogenesis. THs also regulate the hepatic metabolism of nutrients, fluid balance and the cardiovascular system. In cells, TH actions are mediated mainly by nuclear TH receptors (210), which modify gene expression. T3 is the preferred ligand of THR, whereas T4, the serum concentration of which is 100-fold higher than that of T3, undergoes extra-thyroidal conversion to T3. This conversion is catalyzed by 5'-deiodinases (D1 and D2), which are TH-activating enzymes. T4 can also be inactivated by conversion to reverse T3, which has very low affinity for THR, by 5-deiodinase (D3). The regulation of deiodinases, particularly D2, and TH transporters at the cell membrane control T3 availability, which is fundamental for TH action. © 2016 American Physiological Society. Compr Physiol 6:1387-1428, 2016.

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

Cited by 57 publications

References 38 publications

The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function

The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function

Thyroid Hormone Signaling and Cone Photoreceptor Viability

Hypothalamus‐Pituitary‐Thyroid Axis

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