TSH is the most important biomarker in the interpretation of thyroid function in man. Its levels are determined by circulating thyroid hormone (TH) levels that feed back centrally to regulate the expression of the subunits that comprise TSH from the pituitary. The nuclear corepressor 1 (NCoR1), is a critical coregulator of the TH receptor (TR) isoforms. It has been established to play a major role in the control of TSH secretion, because mice that express a mutant NCoR1 allele (NCoRΔID) that cannot interact with the TR have normal TSH levels despite low circulating TH levels. To determine how NCoR1 controls TSH secretion, we first developed a mouse model that allowed for induction of NCoRΔID expression postnatally to rule out a developmental effect of NCoR1. Expression of NCoRΔID postnatally led to a drop in TH levels without a compensatory rise in TSH production, indicating that NCoR1 acutely controls both TH production and feedback regulation of TSH. To demonstrate that this was a cell autonomous function of NCoR1, we expressed NCoRΔID in the pituitary using a Cre driven by the glycoprotein α-subunit promoter (P-ΔID mice). Importantly, P-ΔID mice have low TH levels with decreased TSH production. Additionally, the rise in TSH during hypothyroidism is blunted in P-ΔID mice. Thus, NCoR1 plays a critical role in TH-mediated regulation of TSH in the pituitary by regulating the repressive function of the TR. Furthermore, these studies suggest that endogenous NCoR1 levels in the pituitary could establish the set point of TSH secretion.
"However, previous findings on the role of co-factors in Trh regulation mainly concern TR recruitment of co-repressors, and particularly emphasize the role of NCoR in ligand-independent activation (Becker et al., 2001; Ishii et al., 2004; Satoh et al., 1999). Moreover, it was shown recently that mice expressing a mutant NCoR unable to link TR develop central hypothyroidism comparable to that observed in mice lacking TRH, linking NCoR to TRH and TSH negative regulation (Astapova et al., 2011; Costa-e-Sousa et al., 2012). However, few data are available on RXR interactions with co-regulators when they act as heterodimers (Laflamme et al., 2002; Putcha et al., 2012)). "
[Show abstract][Hide abstract] ABSTRACT: How Retinoid X receptors (RXR) and thyroid hormone receptors (TR) interact on negative TREs and whether RXR subtype specificity is determinant in such regulations is unknown. In a set of functional studies, we analyzed RXR subtype effects in T3-dependent repression of hypothalamic thyrotropin-releasing hormone (Trh). Two-hybrid screening of a hypothalamic paraventricular nucleus cDNA bank revealed specific, T3-dependent interaction of TRs with RXRβ. In vivo chromatin immuno-precipitation showed recruitment of RXRs to the TRE-site 4 region of the Trh promoter in the absence of T3. In vivo overexpression of RXRα in the mouse hypothalamus heightened T3-independent Trh transcription, whereas RXRβ overexpression abrogated this activity. Loss of function of RXRα and β by shRNAs induced inverse regulations. Thus, RXRα and RXRβ display specific roles in modulating T3-dependent regulation of Trh. These results provide insight into the actions of these different TR heterodimerization partners within the context of a negatively regulated gene.
"Thyroid hormones exert powerful feedback inhibition over the TRH response system by inhibiting TRH synthesis and processing in TRH neurons in the paraventricular region of the hypothalamus and decreasing TRH receptors and responses in the pituitary gland (Gershengorn, 1978; Perrone and Hinkle, 1978; Hinkle and Goh, 1982; Segerson et al., 1987; Fekete and Lechan, 2007; Costa and Hollenberg, 2012). Prolonged hypothyroidism leads to a 40-fold increase in TRH receptor mRNA levels in pituitary glands (Costa et al., 2012). In addition, pyroglutamyl peptidase, a highly specific TRH-degrading ectoenzyme, is dramatically increased in hyperthyroid animals (Schomburg and Bauer, 1997; Marsili et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: The pituitary receptor for thyrotropin-releasing hormone (TRH) is a calcium-mobilizing G protein-coupled receptor (GPCR) that signals through Gq/11, elevating calcium, and activating protein kinase C. TRH receptor signaling is quickly desensitized as a consequence of receptor phosphorylation, arrestin binding, and internalization. Following activation, TRH receptors are phosphorylated at multiple Ser/Thr residues in the cytoplasmic tail. Phosphorylation catalyzed by GPCR kinase 2 (GRK2) takes place rapidly, reaching a maximum within seconds. Arrestins bind to two phosphorylated regions, but only arrestin bound to the proximal region causes desensitization and internalization. Phosphorylation at Thr365 is critical for these responses. TRH receptors internalize in clathrin-coated vesicles with bound arrestin. Following endocytosis, vesicles containing phosphorylated TRH receptors soon merge with rab5-positive vesicles. Over approximately 20 min these form larger endosomes rich in rab4 and rab5, early sorting endosomes. After TRH is removed from the medium, dephosphorylated receptors start to accumulate in rab4-positive, rab5-negative recycling endosomes. The mechanisms responsible for sorting dephosphorylated receptors to recycling endosomes are unknown. TRH receptors from internal pools help repopulate the plasma membrane. Dephosphorylation of TRH receptors begins when TRH is removed from the medium regardless of receptor localization, although dephosphorylation is fastest when the receptor is on the plasma membrane. Protein phosphatase 1 is involved in dephosphorylation but the details of how the enzyme is targeted to the receptor remain obscure. It is likely that future studies will identify biased ligands for the TRH receptor, novel arrestin-dependent signaling pathways, mechanisms responsible for targeting kinases and phosphatases to the receptor, and principles governing receptor trafficking.
Frontiers in Neuroscience 12/2012; 6:180. DOI:10.3389/fnins.2012.00180 · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TRβ1. However, the number of known target-genes directly regulated by TRβ1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TRβ1 cistrome in vivo, we expressed a biotinylated TRβ1 in hypo and hyperthyroid mouse livers and used ChIP-seq to identify genomic TRβ1 targets, and correlated this data with gene expression changes. As with other nuclear receptors, the majority of TRβ1 binding sites were not in proximal promoters, but in the gene body of known genes. Remarkably, T3 can dictate changes in TRβ1 binding, with strong correlation to T3-induced gene expression changes, suggesting that differential TRβ1 binding regulates transcriptional outcome. Additionally, DR-4 and DR-0 motifs were significantly enriched at binding sites where T3 induced an increase or decrease in TRβ1 binding respectively, leading to either positive or negative regulation by T3. Taken together this study provides new insights into the mechanisms of transcriptional regulation by TRβ1 in vivo.
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