title: Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system.
abstract: Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TR alpha and TR beta isoforms are products of 2 distinct genes, and the beta 1 and beta 2 isoforms are splice variants of the same gene. Whereas TR alpha 1 and TR beta 1 are widely expressed, expression of the TR beta 2 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 TR beta locus (TR beta-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 TR beta 2 isoform to the function of the endocrine and auditory systems in vivo, we have generated mice with targeted disruption of the TR beta 2 isoform. TR beta 2-null mice have preserved expression of the TR alpha and TR beta 1 isoforms. They develop a similar degree of central resistance to thyroid hormone as TR beta-null mice, indicating the important role of TR beta 2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone gene expression is marginally reduced. In contrast, TR beta 2-null mice exhibit no evidence of hearing impairment, indicating that TR beta 1 and TR beta 2 subserve divergent roles in the regulation of auditory function.
authors.affiliation: Thyroid Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Abel
authors.forename: M E
authors.initials: ME
authors.lastname: Boers
authors.forename: C
authors.initials: C
authors.lastname: Pazos-Moura
authors.forename: E
authors.initials: E
authors.lastname: Moura
authors.forename: H
authors.initials: H
authors.lastname: Kaulbach
authors.forename: M
authors.initials: M
authors.lastname: Zakaria
authors.forename: B
authors.initials: B
authors.lastname: Lowell
authors.forename: S
authors.initials: S
authors.lastname: Radovick
authors.forename: M C
authors.initials: MC
authors.lastname: Liberman
authors.forename: F
authors.initials: F
authors.lastname: Wondisford
mesh_terms: D000818:Animals; D001306:Auditory Pathways / Q000502:physiology* / Q000503:physiopathology; D003433:Crosses, Genetic; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013972:Thyrotropin / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D013972:Thyrotropin; D013006:Growth Hormone; D013974:Thyroxine