Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system
E. Dale Abel, … , M. Charles Liberman, Fredric Wondisford
E. Dale Abel, … , M. Charles Liberman, Fredric Wondisford
Published August 1, 1999
Citation Information: J Clin Invest. 1999;104(3):291-300. https://doi.org/10.1172/JCI6397.
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Article

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

Abstract

Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TRα and TRβ isoforms are products of 2 distinct genes, and the β1 and β2 isoforms are splice variants of the same gene. Whereas TRα1 and TRβ1 are widely expressed, expression of the TRβ2 isoform is mainly limited to the pituitary, triiodothyronine-responsive TRH neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire TRβ locus (TRβ-null) exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the TRβ2 isoform to the function of the endocrine and auditory systems in vivo, we have generated mice with targeted disruption of the TRβ2 isoform. TRβ2-null mice have preserved expression of the TRα and TRβ1 isoforms. They develop a similar degree of central resistance to thyroid hormone as TRβ-null mice, indicating the important role of TRβ2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone gene expression is marginally reduced. In contrast, TRβ2-null mice exhibit no evidence of hearing impairment, indicating that TRβ1 and TRβ2 subserve divergent roles in the regulation of auditory function.

Authors

E. Dale Abel, Mary-Ellen Boers, Carmen Pazos-Moura, Egberto Moura, Helen Kaulbach, Marjorie Zakaria, Bradford Lowell, Sally Radovick, M. Charles Liberman, Fredric Wondisford

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Figure 1

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Targeted disruption of the TRβ2 exon. (a) Schematic representation of th...
Targeted disruption of the TRβ2 exon. (a) Schematic representation of the TRβ2 exon and flanking DNA sequence. The targeting vector was generated by deleting a 1-kb NcoI-SacI fragment encompassing the entire coding exon of the TRβ2 NH2-terminus and the adjacent intron, and by inserting the neomycin resistance gene under the influence of the phosphoglycerate kinase promoter. Homologous integration of the targeting vector was confirmed by Southern blot of genomic DNA digested with NcoI and probed with an α-32P–labeled, 700-bp EcoRI-BamHI DNA fragment that is immediately upstream of the start of the targeting vector. The values 3.4 kb and 4.0 kb represent the expected sizes of the hybridized band in the WT and targeted alleles, respectively. B, BamHI; E, EcoRI; N, NcoI; S, SacI. (b) Representative Southern blot, demonstrating the targeted and WT alleles in KO (–/–), heterozygous (+/–), and WT (+/+) mice.