Feedback Regulation of Thyrotropin‐Releasing Hormone Gene Expression by Thyroid Hormone in the Hypothalamic Paraventricular Nucleus

Lechan, Ronald M.; Kakucska, I.

doi:10.1002/9780470514283.ch10

Cited by 22 publications

(15 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Conversely, increased circulating levels of T 4 cause marked suppression of pro-TRH mRNA in the PVN and a reduction in the secretion of TRH into the portal plexus (63,66), establishing an inverse relationship between thyroid hormone and the biosynthesis and secretion of hypophys- iotropic TRH. The increase or decrease in the amount of hypophysiotropic TRH secreted into the portal system for conveyance to the anterior pituitary as dictated by variations in circulating levels of thyroid hormones, is import to establish the setpoint for feedback regulation by thyroid hormone on anterior pituitary TSH secretion (67)(68)(69).…”

Section: Role Of Hypothalamic Deiodinase In Feedback Regulation Of Hymentioning

confidence: 99%

Role of Thyroid Hormone Deiodination in the Hypothalamus

Lechan

Fekete

2005

Thyroid

Self Cite

View full text Add to dashboard Cite

Iodothyronine deiodinases (D1, D2, and D3) comprise a family of selenoproteins that are involved in the conversion of thyroxine (T(4)) to active triiodothyronine (T(3)), and also the inactivation of both thyroid hormones. The deiodinase enzymes are of critical importance for the normal development and function of the central nervous system. D1 is absent from the human brain, suggesting that D2 and D3 are the two main enzymes involved in the maintenance of thyroid hormone homeostasis in the central nervous system, D2 as the primary T(3)-producing enzyme, and D3 as the primary inactivating enzyme. While the coordinated action of D2 and D3 maintain constant T(3) levels in the cortex independently from the circulating thyroid hormone levels, the role of deiodinases in the hypothalamus may be more complex, as suggested by the regulation of D2 activity in the hypothalamus by infection, fasting and changes in photoperiod. Tanycytes, the primary source of D2 activity in the hypothalamus, integrate hormonal and probably neuronal signals, and under specific conditions, may influence neuroendocrine functions by altering local T(3) tissue concentrations. This function may be of particular importance in the regulation of the hypothalamic-pituitary-thyroid axis during fasting and infection, and in the regulation of appetite and reproductive function. Transient expression of D3 in the preoptic region during a critical time of development suggests a special role for this deiodinase in sexual differentiation of the brain.

show abstract

Section: Role Of Hypothalamic Deiodinase In Feedback Regulation Of Hymentioning

confidence: 99%

Role of Thyroid Hormone Deiodination in the Hypothalamus

Lechan

Fekete

2005

Thyroid

Self Cite

View full text Add to dashboard Cite

show abstract

“…The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback involving thyroid hormones (THs) (T 4 and T 3 ), which are produced by the thyroid gland. The major negative regulator of TSH secretion is T 3 , which directly inhibits the transcription of the TSH-␣ and -␤ subunit genes (1)(2)(3)(4)(5) and TRH (6)(7)(8).…”

mentioning

confidence: 99%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Resistance to thyroid hormone (RTH) is most often due to point mutations in the ␤-isoform of the thyroid hormone (TH) receptor (TR-␤). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-␤ locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T 3 replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T 3 treatment failed to normally suppress these levels. T3 treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T 3 treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.corepressor ͉ homodimer ͉ negative regulation ͉ resistance to thyroid hormone T hyroid-stimulating hormone (thyrotropin or TSH) is a heterodimeric glycoprotein consisting of 2 non-covalently linked protein subunits (TSH-␣ and TSH-␤), synthesized in the pituitary thyrotroph, which regulates the thyroid. TSH-releasing hormone (TRH) is synthesized in the paraventricular nucleus of the hypothalamus and released into the portal circulation, where it regulates the synthesis and glycosylation pattern (bioactivity) of pituitary TSH. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback involving thyroid hormones (THs) (T 4 and T 3 ), which are produced by the thyroid gland. The major negative regulator of TSH secretion is T 3 , which directly inhibits the transcription of the TSH-␣ and -␤ subunit genes (1-5) and TRH (6-8).TH action is mediated by different isoforms of the TH receptor (TR), which are members of the nuclear receptor superfamily of ligand-modulated transcription factors. Two genes, by alternative splicing and transcriptional start site utilization, express the known ligand-binding TR isoforms, TR-␣1, TR-␤1, TR-␤2, and TR-␤3. Negative regulation of the HPT axis is principally mediated by the ␤ isoform of the TR (9-13).On genes with a positive TH response element, TR interacts with corepressor proteins (CoRs) in the absence of ligand, and this...

show abstract

“…10). Although this was initially unexpected, TH has been shown to have an inhibiting effect on expression of TRE regulated genes (6,13,42,51,68).…”

Section: Retinoid Signaling Pathwaymentioning

confidence: 99%

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

Noble

Babiuk²,

Clugston³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

110

View full text Add to dashboard Cite

Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported. retinoid signaling CONGENITAL DIAPHRAGMATIC HERNIA (CDH) is a serious developmental abnormality that occurs in ϳ1 in 2,500 live births (41). The most commonly observed type of this anomaly is the Bochdalek hernia, characterized by incomplete formation of the posterolateral diaphragm and the invasion of the thoracic cavity by abdominal viscera. The ensuing abnormal fetal breathing movements and physical constraints on the developing lungs and heart contribute to pulmonary and left ventricular hypoplasia and pulmonary hypertension (20,35,37). Despite improved treatment strategies, CDH continues to have significant morbidity and mortality (50,69). Insights into the pathogenesis of the diaphragm defect have arisen from teratogenic, dietary, and genetic rodent models of Bochdalek CDH in conjunction with examination of human postmortem tissue (17). Specifically, the initial diaphragmatic defect appears to occur early (before week 5) during the embryogenesis of the amuscular component of the primordial diaphragm, the pleuroperitoneal fold. Much less is known about the etiology of CDH. However, considering the partial similarities between the pathologies observed in the teratogenic nitrofen-induced rat model and infants with CDH (1, 19, 40), the possibility that a common underlying etiology exists has received consideration. There have been a number of hypotheses put forth to explain the teratogenic effects of nitrofen. The retinoid hypothesis suggests that abnormalities in retinoid signaling, or regulation of the retinoid pathway, lead to the development of the primary diaphragm defect and potentially to direct effects on lung development (reviewed in Ref. 33). Other studies have suggested that nitrofen alte...

show abstract

Feedback Regulation of Thyrotropin‐Releasing Hormone Gene Expression by Thyroid Hormone in the Hypothalamic Paraventricular Nucleus

Cited by 22 publications

References 62 publications

Role of Thyroid Hormone Deiodination in the Hypothalamus

Role of Thyroid Hormone Deiodination in the Hypothalamus

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

Contact Info

Product

Resources

About