Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system

Abel, E. Dale; Boers, Mary Ellen; Pazos‐Moura, Carmen C.; Moura, Egberto Gaspar de; Kaulbach, Helen C.; Zakaria, Marjorie; Lowell, Bradford B.; Radovick, Sally; Liberman, M. Charles; Wondisford, Fredric E.

doi:10.1172/jci6397

Cited by 187 publications

(109 citation statements)

References 51 publications

(58 reference statements)

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“…The DNA Binding Affinity of the GS125 TR-␤ Is Reduced on Both Positive TRE and Negative TREs-Recent cell culture and TR knockout model studies suggest that the ␤2 isoform of the thyroid hormone receptor (TR-␤2) plays the predominant role in the feedback regulation of the H-P-T axis (43)(44)(45). Therefore, we introduced the GS125 mutation into the TR-␤2 isoform and used it for the following experiments.…”

Section: Resultsmentioning

confidence: 99%

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Shibusawa

Hollenberg

Wondisford

2003

Journal of Biological Chemistry

117

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The ␤ isoform of thyroid hormone receptor (TR-␤) has a key role in the feedback regulation of the hypothalamic-pituitary-thyroid (H-P-T) axis. The mechanism of trans-repression of the hypothalamic thyrotropin-releasing hormone (TRH) and pituitary thyroid-stimulating hormone (TSH) subunit genes, however, remains poorly understood. A number of distinct mechanisms for TR-␤-mediated negative regulation by thyroid hormone have been proposed, including those that require and do not require DNA binding. To clarify the importance of DNA binding in negative regulation, we constructed a DNA-binding mutant of TR-␤ in which two amino acids within the P box were altered (GSG for EGG) to resemble that found in the glucocorticoid receptor (GR). We termed this mutant GS125, and as expected, it displayed low binding affinities for positive and negative thyroid hormone-response element (pTRE and nTRE, respectively) in gel-mobility shift assays. In transient transfection assays, the GS125 mutant abolished transactivation on three classic pTREs (DR؉4, LAP, and PAL) and all negatively regulated promoters in the H-P-T axis (TRH, TSH-␤, and TSH-␣). However, GS125 TR-␤ bound to a composite TR/GR-response element and was fully functional on this hybrid TR/GR-response element. Moreover, the GS125 TR-␤ mutant displayed normal interactions with transcriptional cofactors in mammalian twohybrid assays. These data do not support a DNA-binding independent mechanism for thyroid hormone negative regulation in the H-P-T axis.The synthesis and secretion of thyroid hormones are exquisitely regulated by a negative feedback system that involves the hypothalamus, pituitary, and thyroid gland (the hypothalamicpituitary-thyroid axis: H-P-T axis). 1 The synthesis of thyrotropin-releasing hormone (TRH), produced in the paraventricular nucleus of the hypothalamus, and the ␣ and ␤ subunits of thyrotropin (thyroid-stimulating hormone; TSH) in the anterior lobe of the pituitary is inhibited at the transcriptional level by thyroid hormone (T 3 ) (1-4). Negative regulation of gene expression by T 3 is an integral part of the function in the H-P-T axis, and these effects are mediated by the ␤ isoform of the thyroid hormone receptors (TR-␤). Of the ␤ isoforms, TR-␤2 is quantitatively and functionally more important than TR-␤1 in regulating the hypothalamus and pituitary (5-8). The molecular mechanisms responsible for TR-mediated negative regulation of target genes are not well understood.In the traditional model of TR action, TR regulates gene expression by binding to specific thyroid hormone-response elements (TRE) on target genes. A number of artificial and natural positive thyroid hormone-response elements (pTREs) have been described, and they can be classified based on the half-site arrangement in the element: DRϩ4, PAL, and LAP (LYS) (9 -11). On target genes negatively regulated by T 3 , response elements (nTREs) have been described in the TRH and TSH-␤ subunit genes (12-17). In these nTREs, TR bound as a monomer to widely spaced half-sites or in the case of...

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Section: Resultsmentioning

confidence: 99%

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Shibusawa

Hollenberg

Wondisford

2003

Journal of Biological Chemistry

117

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“…Right panel: protein products. For TR␤2 Ϫ/Ϫ , exon 1 of the TR␤2 isoform is ablated, leaving the TR␤1 intact (Abel et al, 1999). For TR␤ GS/GS , exon 3 is mutated by changing residues in the P-box region of the first Zn-finger that compromise DNA binding of both TR␤1 and TR␤2 (Shibusawa et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Three transgenic lines carrying mutations were analyzed for their effects on S opsin expression: In the TR␤2 Ϫ/Ϫ mouse, the first exon of TR␤2 has been eliminated to make a TR␤2 null mutation. In this animal, the TR␤1 receptor remains unaltered and is expressed (Abel et al, 1999). In the TR␤ GS/GS mouse, two mutations in the DNA binding P-box region compromise the receptor's ability to bind DNA at thyroid hormone response elements (TREs); the mutations do not disrupt the Zn-finger structure but do affect both TR␤1 and TR␤2 function (Shibusawa et al, 2003).…”

Section: Dna Binding and T3 Ligand Binding Are Required For Tr␤2 To Amentioning

confidence: 99%

“…The generation and characterization of the TR␤2 Ϫ/Ϫ knockout, the TR␤ GS/GS , and the TR␤ ⌬337T/⌬337T knockin mouse lines have been reported (Abel et al, 1999;Hashimoto et al, 2001;Shibusawa et al, 2003), respectively. Mice were genotyped by Southern blotting (TR␤ ⌬337T/⌬337T ) or PCR as described (Abel et al, 1999;Hashimoto et al, 2001;Shibusawa et al, 2003; see the legend to Fig. 5).…”

Section: Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

Applebury

Farhangfar

Glösmann

et al. 2007

Developmental Dynamics

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Cone photoreceptors in the murine retina are patterned by dorsal repression and ventral activation of S opsin. TR␤2, the nuclear thyroid hormone receptor ␤ isoform 2, regulates dorsal repression. To determine the molecular mechanism by which TR␤2 acts, we compared the spatiotemporal expression of TR␤2 and S opsin from embryonic day (E) 13 through adulthood in C57BL/6 retinae. TR␤2 and S opsin are expressed in cone photoreceptors only. Both are transcribed by E13, and their levels increase with cone genesis. TR␤2 is expressed uniformly, but transiently, across the retina. mRNA levels are maximal by E17 at completion of cone genesis and again minimal before P5. S opsin is also transcribed by E13, but only in ventral cones. Repression in dorsal cones is established by E17, consistent with the occurrence of patterning during cone cell genesis. The uniform expression of TR␤2 suggests that repression of S opsin requires other dorsalspecific factors in addition to TR␤2. The mechanism by which TR␤2 functions was probed in transgenic animals with TR␤2 ablated, TR␤2 that is DNA binding defective, and TR␤2 that is ligand binding defective. These studies show that TR␤2 is necessary for dorsal repression, but not ventral activation of S opsin. TR␤2 must bind DNA and the ligand T3 (thyroid hormone) to repress S opsin. Once repression is established, T3 no longer regulates dorsal S opsin repression in adult animals. The transient, embryonic action of TR␤2 is consistent with a role (direct and/or indirect) in chromatin remodeling that leads to permanent gene silencing in terminally differentiated, dorsal cone photoreceptors.

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“…Heterozygotes are normal and homozygotes have, in addition to the characteristic thyroid test abnormalities, sensorineural deafness and monochromatic vision, indicating that the deaf-mutism and color blindness in humans can be fully explained by the complete absence of TRβ. These mice allowed in-depth investigations establishing that TRβ2 deficiency was responsible for the color blindness [60] but not for the hearing loss [61]. TRβKO mice have increased heart rate that normalizes with reduction on the TH level [62,63].…”

Section: Trβ Gene Manipulationsmentioning

confidence: 99%

Syndromes of Reduced Sensitivity to Thyroid Hormone

Weiss

Dumitrescu

Refetoff

2010

Genetic Diagnosis of Endocrine Disorders

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Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system

Cited by 187 publications

References 51 publications

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

Syndromes of Reduced Sensitivity to Thyroid Hormone

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