Thyroid hormone receptors TRα1 and TRβ differentially regulate gene expression of<i>Kcnq4</i>and prestin during final differentiation of outer hair cells

Winter, Harald; Braig, Claudia; Zimmermann, Ulrike; Geisler, Hyun Soon; Fränzer, Jürgen Theodor; Weber, Thomas; Ley, Matthias; Engel, Jutta; Knirsch, Martina; Bauer, Karl; Christ, Shawn E.; Walsh, Edward J.; McGee, JoAnn; Köpschall, Iris; Rohbock, Karin; Knipper, Marlies

doi:10.1242/jcs.03013

Cited by 73 publications

(69 citation statements)

References 72 publications

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“…Using KO mice, Winter et al (18) previously characterized a similar situation in some cells of the inner ear where prestin and KCNQ4 were specifically regulated by TR␤ and TR␣, respectively. In this case, neither ChIP nor transfection experiments were performed to show a direct regulation, but both receptors bound to the two isolated TREs in EMSA.…”

Section: Th Stimulate Chrebp Expression In a Tr␤-dependent Manner In mentioning

confidence: 96%

“…Importantly in the organs where they are co-expressed, their function is not necessarily redundant. Recently, two genes were described to be specifically regulated by either TR␣1 or TR␤ (18) in the outer hair of the developing cochlea, suggesting that each receptor might regulate its own set of targets in response to TH. The lipogenic effect of TH has been attributed to TR␤ because in the liver, TH regulation of FAS, ACC, Spot14, and ME is lost in TR␤ Ϫ/Ϫ mice (13).…”

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confidence: 99%

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Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner

Gauthier

Billon

Bissler

et al. 2010

Journal of Biological Chemistry

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De novo lipogenesis allows the synthesis of new molecules of fatty acids from acetyl CoA. High glucose and insulin concentrations induce this process, converting the excess energy into triglycerides, a more relevant molecule for storage purposes. In rodents, both liver and WAT 3 are efficient sites for lipogenesis. The synergic actions of insulin and glucose on the expression of lipogenic genes are mediated by key transcription factors.

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Section: Th Stimulate Chrebp Expression In a Tr␤-dependent Manner In mentioning

confidence: 96%

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confidence: 99%

Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner

Gauthier

Billon

Bissler

et al. 2010

Journal of Biological Chemistry

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“…For example, although the fast-activating potassium conductance (I K,f ) in inner hair cells of TRβ-null mice, as well as calcium channel currents and resting membrane potentials in hypothyroid rats are developmentally delayed, adultlike values are eventually achieved (Rusch et al 1998(Rusch et al , 2001Brandt et al 2007). In OHCs of TRβ-null and Tshr hyt mutant mice, expression patterns of the motor protein, prestin (Slc26a5), although delayed, ultimately mature (Winter et al 2006, as do nonlinear capacitance and electromotility, respectively (Rusch et al 1998;Walsh et al 2003). This, of course, is not always the case.…”

Section: Fig 4 Comparisons Of Adult Valuesmentioning

confidence: 99%

“…This, of course, is not always the case. While the expression of prestin is upregulated (Weber et al 2002) via TRβ, the expression of the potassium channels, KCNQ4, BK, and SK2, for example, are actually repressed via unbound TRα1 in the absence of TH (Winter et al 2006 and may be the source of permanent deficits in congenital, profound hypothyroidism. These findings emphasize the importance of tracking the development of the hypothyroid cochlea to its end point.…”

Section: Fig 4 Comparisons Of Adult Valuesmentioning

confidence: 99%

The Influence of Thyroid Hormone Deficiency on the Development of Cochlear Nonlinearities

Song

McGee

Walsh

2008

JARO

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It is well known that failure to treat severe congenital hypothyroidism leads to profound auditory disability, and it has been suggested that an intracochlear defect, or defects, associated with the condition diminishes the efficacy of an active, physiologically vulnerable nonlinear transduction process commonly referred to as cochlear amplification. We address this question directly by tracking the development of threshold-frequency (tuning) curves and two-tone suppression in hypothyroid, Tshr mutant mice born to hypothyroid dams and comparing those findings with findings observed in euthyroid mice. Like sharp tuning, two-tone suppression is a product of transduction nonlinearity and is a useful indicator of the functional status of cochlear amplification. In contrast to euthyroid mice that acquire sharp tuning, normal two-tone suppression, and adultlike sensitivity by the end of the third postnatal week, as shown in earlier studies, hypothyroid mice remained grossly insensitive to sound throughout life. In addition, tuning was generally broad in hypothyroid mice, tuning curve "tips" were frequently missing, and two-tone suppression was rarely observed. However, unlike tip thresholds, tuning curve "tail" thresholds, a feature that reflects the functional status of passive elements of transduction, acquired normal values over a roughly 2-month postnatal time period. These observations collectively suggest that active transduction micromechanics, at least in the frequency region studied here, are profoundly affected by thyroid hormone and support speculation that abnormal outer hair cell function may be the cause of the primary, enduring peripheral auditory defect associated with profound, congenital hypothyroidism in the Tshr mutant mouse.

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“…Although rarely considered, this proposal would explain why, in tissues where TRα1 and TRβ1 expression is apparently balanced, a mutation of only one of the genes is sufficient to alter the phenotype. It would also account for several puzzling observations: in the inner ear outer hair cells, Prestin expression is altered by mutation of TRβ1, but not of TRα1, whereas the opposite is observed for Kcnq4 (25,26). In hepatocytes, where TRβ1 represents more than 80% of the T3 receptors, a fraction of the T3 responsive genes cannot be activated by a TRβ selective ligand (27).…”

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confidence: 99%

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

Chatonnet

Guyot

Galand

et al. 2013

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

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TRα1 and TRβ1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3′,5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRβ1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRβ1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.

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Thyroid hormone receptors TRα1 and TRβ differentially regulate gene expression ofKcnq4and prestin during final differentiation of outer hair cells

Cited by 73 publications

References 72 publications

Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner

Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner

The Influence of Thyroid Hormone Deficiency on the Development of Cochlear Nonlinearities

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

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