scholarly journals Thyroid Hormone Receptors Control Developmental Maturation of the Middle Ear and the Size of the Ossicular Bones

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1548-1560 ◽  
Author(s):  
Emily A. Cordas ◽  
Lily Ng ◽  
Arturo Hernandez ◽  
Masahiro Kaneshige ◽  
Sheue-Yann Cheng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Inner Ear ◽  
Middle Ear ◽  
Hormone Receptors ◽  
Dominant Negative ◽  
Thyroid Hormone Receptors ◽  
Auditory Thresholds ◽  
Auditory Development ◽  
Genes Encoding

Thyroid hormone is critical for auditory development and has well-known actions in the inner ear. However, less is known of thyroid hormone functions in the middle ear, which contains the ossicles (malleus, incus, stapes) that relay mechanical sound vibrations from the outer ear to the inner ear. During the later stages of middle ear development, prior to the onset of hearing, middle ear cavitation occurs, involving clearance of mesenchyme from the middle ear cavity while the immature cartilaginous ossicles attain appropriate size and ossify. Using in situ hybridization, we detected expression of Thra and Thrb genes encoding thyroid hormone receptors α1 and β (TRα1 and TRβ, respectively) in the immature ossicles, surrounding mesenchyme and tympanic membrane in the mouse. Thra+/PV mice that express a dominant-negative TRα1 protein exhibited deafness with elevated auditory thresholds and a range of middle ear abnormalities including chronic persistence of mesenchyme in the middle ear into adulthood, markedly enlarged ossicles, and delayed ossification of the ossicles. Congenitally hypothyroid Tshr−/− mice and TR-deficient Thra1−/−;Thrb−/− mice displayed similar abnormalities. These findings demonstrate that middle ear maturation is TR dependent and suggest that the middle ear is a sensitive target for thyroid hormone in development.

scholarly journals Differential Recruitment of Nuclear Coregulators Directs the Isoform-Dependent Action of Mutant Thyroid Hormone Receptors

2011 ◽  
Vol 25 (6) ◽  
pp. 908-921 ◽  
Author(s):  
Laura Fozzatti ◽  
Changxue Lu ◽  
Dong-Wook Kim ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Biological Activities ◽  
Liver Lipid ◽  
Dominant Negative ◽  
Mutant Mice ◽  
Regulatory Proteins ◽  
Thyroid Hormone Receptors ◽  
Dominant Negative Mutation

Abstract Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TRα1 and TRβ1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TRα1 (Thra1PV mice) or β1 (ThrbPV mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-dependent functions in vivo. Here we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that distinct 33 nuclear proteins including nuclear receptor corepressor (NCoR1) and six other proteins preferentially associated with TRα1PV or TRβ1PV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is subtype dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of Thra1PV and ThrbPV mice was further explored. NCoR1 preferentially interacted with TRα1PV rather than with TRβ1PV. NCoR1 was recruited more avidly to the thyroid hormone response element-bound TRα1PV than to TRβ1PV in the promoter of the CCAAT/enhancer-binding protein α gene to repress its expression in the liver of Thra1PV mice, but not in ThrbPV mice. This preferential recruitment of NCoR1 by mutant isoforms could contribute, at least in part, to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins.

scholarly journals Hematopoiesis in aged female mice devoid of thyroid hormone receptors

2020 ◽  
Vol 244 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Ángela Sánchez ◽  
Constanza Contreras-Jurado ◽  
Diego Rodríguez ◽  
Javier Regadera ◽  
Susana Alemany ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
B Cell ◽  
Knockout Mice ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Thyroid Hormone Receptors ◽  
Female Mice

Hypothyroidism is often associated with anemia and immunological disorders. Similar defects are found in patients and in mice with a mutated dominant-negative thyroid hormone receptor α (TRα) and in knockout mice devoid of this receptor, suggesting that this isoform is responsible for the effects of the thyroid hormones in hematopoiesis. However, the hematological phenotype of mice lacking also TRβ has not yet been examined. We show here that TRα1/TRβ-knockout female mice, lacking all known thyroid hormone receptors with capacity to bind thyroid hormones, do not have overt anemia and in contrast with hypothyroid mice do not present reduced Gata1 or Hif1 gene expression. Similar to that found in hypothyroidism or TRα deficiency during the juvenile period, the B-cell population is reduced in the spleen and bone marrow of ageing TRα1/TRβ-knockout mice, suggesting that TRβ does not play a major role in B-cell development. However, splenic hypotrophy is more marked in hypothyroid mice than in TRα1/TRβ-knockout mice and the splenic population of T-lymphocytes is not significantly impaired in these mice in contrast with the reduction found in hypothyroidism. Our results show that the overall hematopoietic phenotype of the TRα1/TRβ-knockout mice is milder than that found in the absence of hormone. Although other mechanism/s cannot be ruled out, our results suggest that the unoccupied TRs could have a negative effect on hematopoiesis, likely secondary to repression of hematopoietic gene expression.

scholarly journals Thyroid hormone receptors in chick retinal development: differential expression of mRNAs for alpha and N-terminal variant beta receptors

Development ◽  
1992 ◽  
Vol 114 (1) ◽  
pp. 39-47 ◽  
Author(s):  
M. Sjoberg ◽  
B. Vennstrom ◽  
D. Forrest
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Retinal Development ◽  
Outer Nuclear Layer ◽  
In Situ Hybridisation ◽  
Thyroid Hormone Receptors ◽  
Rat Pituitary ◽  
Beta 2 ◽  
Low Levels

Thyroid-hormone-dependent development of the neuroretina has principally been described in amphibia. Here, we show by in situ hybridisation that mRNAs coding for three distinct thyroid hormone receptors (TRs), TR alpha and two TR beta variants, are differentially expressed during chick retinal development. We isolated a cDNA for a novel N-terminal variant of chick TR beta (cTR beta 2) that is predominantly expressed in retinal development. Interestingly, in its N-terminal A/B domain cTR beta 2 is 70% homologous to the rat pituitary-specific TR beta 2. Expression of cTR beta 2 mRNA was high at embryonic day 6 (E6) in the retinal outer nuclear layer (ONL) and decreased to low levels at hatching. mRNA for the previously described chick beta receptor, cTR beta 0, was expressed at low levels in both the ONL and the inner nuclear layer (INL) after E10. In contrast, cTR alpha expression occurred in the ONL, INL and ganglion cell layer at intermediate and later stages. Finally, cTR beta 2 confers a stronger trans-activation of reporter gene transcription than cTR beta 0. The distinctive kinetics and localisation of TR alpha and beta gene expression suggest cell- and stage-specific functions for TRs, both individually and in combinations, in chick neuroretinal development.

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