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

Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TR alpha and TR beta isoforms are products of 2 di stinct genes, and, the beta 1 and beta 2 isoforms are splice variants of th e same gene. Whereas TR alpha 1 and TR beta 1 are widely expressed, express ion of the TR beta 2 isoform is mainly limited to the pituitary, triiodothy ronine-responsive TRH neurons, the developing inner ear, and the retina. Mi ce with targeted disruption of the entire TR beta locus (TR beta-null) exhi bit elevated thyroid hormone levels as a result of abnormal central regulat ion 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 o f the TR beta 2 isoform. TR beta 2-null mice have preserved expression of t he TR alpha and TR beta 1 isoforms. They develop a similar degree of centra l resistance to thyroid hormone as TR beta-null mice, indicating the import ant role of TR beta 2 in the regulation of the hypothalarnic-pituitary-thyr oid 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.