Dominant Inhibition of Thyroid Hormone Action Selectively in the Pituitary of Thyroid Hormone Receptor-β Null Mice Abolishes the Regulation of Thyrotropin by Thyroid Hormone

Abstract

Thyroid hormones, T4 and T3, regulate their own production by feedback inhibition of TSH and TRH synthesis in the pituitary and hypothalamus when T3 binds to thyroid hormone receptors (TRs) that interact with the promoters of the genes for the TSH subunit and TRH. All TR isoforms are believed to be involved in the regulation of this endocrine axis, as evidenced by the massive dysregulation of TSH production in mice lacking all TR isoforms. However, the relative contributions of TR isoforms in the pituitary vs. the hypothalamus remain to be completely elucidated. Thus, to determine the relative contribution of pituitary expression of TR-alpha in the regulation of the hypothalamic-pituitary-thyroid axis, we selectively impaired TR-alpha function in TR-beta null mice (TR-beta-/-) by pituitary restricted expression of a dominant negative TR-beta transgene harboring a delta337T mutation. These animals exhibited 10-fold and 32-fold increase in T4 and TSH concentrations, respectively. Moreover, the negative regulation of TSH by exogenous T3 was completely absent and a paradoxical increase in TSH concentrations and TSH-beta mRNA was observed. In contrast, prepro-TRH expression levels in T3-treated TR-beta-/- were similar to levels observed in the delta337/TR-beta-/- mice, and ligand-independent activation of TSH in hypothyroid mice was equivalently impaired. Thus, isolated TR-beta deficiency in TRH paraventricular hypothalamic nucleus neurons and impaired function of all TRs in the pituitary recapitulate the baseline hormonal disturbances that characterize mice with complete absence of all TRs.

The p160 Coactivator PAS-B Motif Stabilizes Nuclear Receptor Binding and Contributes to Isoform-specific Regulation by Thyroid Hormone Receptors

“…The different TR isoforms play distinct roles in endocrine physiology (14,17,(21)(22)(23)(24). The TR␤2 isoform in the hypothalamus and pituitary plays a particularly crucial role in a negative feedback regulatory loop by which increases in circulating T 3 /T 4 thyroid hormone levels result in suppression of thyroid releasing hormone and thyroid stimulating hormone synthesis, thereby restoring proper endocrine homeostasis (19,20,22,(25)(26)(27)(28)(29).…”

Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture

“…Based on knockout and knockin experiments, TRα was found to influence cardiac functions, thermogenesis, haematopoiesis, and the maturation of intestines and bones (O'Shea et al, 2005;Plateroti et al, 2006). TRβ is crucial for normal, physiological endocrine and sensory functions such as those regulated by the hypothalamic-pituitary-thyroid axis, hepatic reactions to T3, behaviour, audition, colour sensation, and tactile senses (Amma et al, 2001;Ng et al, 2001;Flores-Morales et al, 2002;Abel et al, 2003;Esaki et al, 2003;Siesser et al, 2005). TRα and TRβ, however, can be co-expressed in the same tissues and can substitute for each other's function to a certain extent (Gothe et al, 1999).…”

Studies of Complex Biological Systems with Applications to Molecular Medicine: The Need to Integrate Transcriptomic and Proteomic Approaches

“…In mammals, two genes encoding TRs have been characterized, c-erb Aα and c-erb Aβ [79][80][81], and these encode several proteins (α and β isoforms) with different binding properties and patterns of tissue expression. For example, c-Erb Aβ1 is expressed across a wide range of tissues, while c-ErbAβ2 is found almost exclusively in the pituitary, where it inhibits thyrotrophin (TSH) α-and β-subunit gene transcription [82] by binding to negative TREs present on these genes [83,84]. New information on the mechanisms of action of THs have been obtained from TR gene knockout (KO) and knock-in studies [85].…”