Distinct genetic signatures for variability in total and free serum thyroxine levels in four sets of recombinant inbred mice

C3H/He and BALB/c mice have elevated serum thyroxine levels associated with low deiodinase type-1 activity whereas C57BL/6 (B6) mice have low thyroxine levels and elevated deiodinase type-1 activity. High-resolution genetic maps are available for four sets of recombinant inbred (RI) mice derived from B6 parents bred to C3H/He, BALB/c, DBA/2, or A strains. Total and free T4 (T-T4 and F-T4) levels in females from these RI sets (BXH, CXB, BXD, and AXBXA) were analyzed to test two hypotheses: first, serum T4 variability is linked to the deiodinase type-1 gene; second, because of their shared B6 parent, the RI sets will share linkages responsible for T-T4 or F-T4 variability. A number of chromosomes (Chr) and loci were linked to T-T4 (Chr 1, 4, 13, 11) or F-T4 (Chr 1, 6, 13, 18, 19). Linkage between T-T4 and Chr 4 was limited to CXB and BXH strains, but the locus was distinct from the deiodinase type-1 gene. Surprisingly, many linkages were unique providing "genetic signatures" for T-T4 or F-T4 in each set of RI mice. Indeed, the strongest linkage between T-T4 (or F-T4) and a Chr 2 locus (logarithm of the odds scores >4.4) was only observed in AXBXA strains. Some loci corresponded to genes/Chr associated in humans with variable TSH or T-T4 levels. Unlike inbred mice, human populations are extremely diverse. Consequently, our data suggest that the contributions of unique chromosomes/loci controlling T-T4 and F-T4 in distinct human subgroups are likely to be "buried" in genetic analyses of heterogeneous human populations.     

Central hypothyroidism is associated with advanced age in male Fischer 344/N rats: in vivo and in vitro studies.

We investigated age-related alterations in hypothalamic-pituitary-thyroid function in a series of in vivo and in vitro studies in 2-, 8-, 18-, and 24-month-old male Fischer 344/N (F344/N) rats. Thyroid histology showed progressive follicular loss with advancing age; this was associated with significant and progressive decrements in plasma levels of free T4 and free T3, but not immunoreactive TSH, which remained unchanged with age. This was accompanied by a progressive age-dependent loss in in vivo responsivity of the thyrotroph to synthetic TRH and a paradoxically augmented response of GH to this peptide in the oldest rats. Steady state levels of prepro-TRH mRNA in the hypothalamic paraventricular nucleus were decreased with age, whereas TRH content in and in vitro secretion by whole hypothalami remained unchanged. Both anterior pituitary steady state TSH beta-subunit mRNA levels and TSH content were decreased with age. Taken together, these data suggest that aging in male F344/N rats is associated with a progressive, centrally mediated decrease in thyroid function. The relative contributions to this phenomenon of age-related alterations in supra-hypothalamic and/or hypothalamic vs. pituitary thyrotropic function remain to be determined, as do the relationships between changes in hypothalamic-pituitary-thyroid function and those in aging per se.     

Genetic determination of cardiac mass in normotensive rats: results from an F344xWKY cross

Genetic determinants affect adult cardiac mass and the predisposition to develop cardiac hypertrophy. The aim of this study was to identify quantitative trait loci (QTL) that control heart and left ventricular (LV) weight by use of normotensive inbred rat strains that differ in their adult cardiac mass phenotype. We studied 126 male F2 rats derived from a cross of normotensive Wistar-Kyoto and Fischer 344 rats. At 12 weeks of age, total heart weight and LV weight were measured. Genomic DNA from these animals was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). In this cross, the genetic contribution to total heart weight variation was 56%, and the genetic contribution for LV weight was 55%. Using the Mapmaker/QTL computer package, we identified a significant QTL on chromosome 3 with a log10 likelihood (LOD) score of 4.8, which accounted for 16.5% of the total variance of LV weight. This QTL was centered close to the marker D3Rat29. The QTL was also found to be significantly linked with total heart weight (LOD=4.4). These data provide the first demonstration of a QTL on chromosome 3 that plays a role in determining the difference in LV mass between normotensive Fischer 344 and Wistar- Kyoto inbred rat strains. The prostaglandin synthase 1 gene is located within the QTL.     

Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone, and insulin infusion in a rabbit model of prolonged critical illness

Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.h GHRP-2 and 60 microg/kg.h TRH, i.v. (n=9); or 3.5 mg/kg rhGH, s.c. (n=7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose below 180 mg/dl. Endocrine function and biochemical organ system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ system function, hyperglycemia, and insulin requirement were equal in the three groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on d 1. After 4 d, rGH secretion and T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase and a decrease in type 3 deiodinase. Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH without altering thyroid hormone levels. Unlike GHRP-2+TRH, rhGH down-regulated liver type 3 deiodinase and did not affect type 1 deiodinase. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human model, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.     

Expression of type 2 iodothyronine deiodinase in human osteoblast is stimulated by thyrotropin

Thyroid hormones play important roles in bone growth, development, and turnover. To exert its biological activity, T(4) needs to be converted to T(3) by iodothyronine deiodinase. In human thyroid gland as well as rat brown adipose tissue, type 2 iodothyronine deiodinase (D2) expression is regulated by a TSH receptor-cAMP-mediated mechanism. TSH receptor knockout mice demonstrated the direct effects of TSH on bone via TSH receptors found on osteoblast and osteoclast precursors. In the present study we investigated the possible expression and function of iodothyronine deiodinase and TSH receptors in human osteoblast-like osteosarcoma (SaOS-2) cells and normal human osteoblast (NHOst) cells. Iodothyronine deiodinase activity was detected in SaOS-2 cells and NHOst cells, and all of the characteristics of deiodinating activity were compatible with those of D2. Northern analysis demonstrated D2 mRNA expression in SaOS-2 cells and NHOst cells. D2 mRNA levels as well as D2 activities were rapidly increased by dibutyryl cAMP or forskolin in SaOS-2 cells and NHOst cells. TSH receptor mRNA was demonstrated in SaOS-2 cells and NHOst cells, and D2 mRNA and D2 activity were stimulated by TSH in both cells. In addition, all T(3) receptor isoforms were detected by RT-PCR in SaOS-2 cells and NHOst cells. The present results indicate the expression of functional TSH receptors and D2 in human osteoblasts and suggest previously unrecognized roles of TSH receptors and local T(3) production by D2 in the pathophysiology of human osteoblasts.     

Thyroid axis function and dysfunction in critical illness

Acutely ill patients typically present with low circulating T3 and increased reverse T3. When illness is severe and prolonged, also pulsatile TSH secretion and circulating T4 levels are low. This constellation of changes within the thyroid axis is referred to as the low T3 syndrome or non-thyroidal illness syndrome (NTI), and comprises both peripheral and central alterations in the thyroid axis. Acute alterations are dominated by changes in thyroid hormone binding, in thyroid hormone uptake by the cell and in the activity of the type-1 and type-3 deiodinase enzymes. Prolonged critical illness is associated with a neuroendocrine dysfunction characterized by suppressed hypothalamic thyrotropin-releasing hormone (TRH) expression, resulting in reduced stimulation of the thyrotropes whereby thyroidal hormone release is impaired. During prolonged critical illness, several tissue responses could be interpreted as compensatory to low thyroid hormone availability, such as increased expression of monocarboxylate transporters, upregulation of type 2 deiodinase activity and increased sensitivity at the receptor level. Whether the low T3 syndrome should be treated and which compound should be used remains to be further studied.     

Genomewide linkage analysis identifies novel genetic Loci for lung function in mice

RATIONALE: Pulmonary function, including lung volumes and compliance, may be genetically determined, but few genetic polymorphisms have been identified that control these traits. We used an experimental approach and performed the first whole genome scan for pulmonary function in mice. OBJECTIVES AND METHODS: To identify novel chromosomal regions contributing to lung function, quantitative trait locus linkage analysis was applied in N(2) backcross and F(2) intercross mice derived from two inbred strains-C3H/HeJ and JF1/Msf-with extremely divergent phenotypes. MAIN RESULTS: Significant linkages to total lung capacity with LOD (logarithm of the odds) scores up to 6.0 were detected on chromosomes 15 and 17, to dead space volume and lung compliance on chromosomes 5 and 15 (LOD scores higher than 4.0), to lung compliance also on chromosome 19 (LOD score of 5.8), and to diffusing capacity on chromosomes 15 and 17 (LOD scores up to 5.0). The region of interest on chromosome 17 near D17Mit133 contains a syntenic region to human chromosome 6q27, which was recently identified to be linked to lung function in humans. The identified intervals harbor valuable candidate genes, such as the relaxin1 and transforming growth factor beta receptor 3 gene, which revealed missense polymorphisms between the parental strains. CONCLUSION: The study provides evidence for linkage of different measures of lung function on murine chromosomes 5, 15, 17, and 19 and suggests novel candidate genes that may also affect the expression of human pulmonary function.     

Probing the genetic basis for thyrotropin receptor antibodies and hyperthyroidism in immunized CXB recombinant inbred mice

Immunization with adenovirus encoding the TSH receptor (TSHR) or its A-subunit induces Graves' hyperthyroidism in BALB/c and BALB/c x C57BL/6 offspring but not C57BL/6 mice. High-resolution genetic maps are available for 13 recombinant inbred CXB strains generated from BALB/c x C57BL/6 progeny by repeated brother x sister matings to establish fully inbred lines. CXB strains were studied before and after A-subunit adenovirus immunization for TSHR antibodies (TBI, inhibition of TSH binding), serum T4, and thyroid histology. All strains developed TBI activity (at variable levels), six strains became hyperthyroid, and one was overtly thyrotoxic. No low TBI responders became hyperthyroid, but high TBI did not predict hyperthyroidism. Preimmunization T4 levels varied in different CXB strains and was unrelated to subsequent T4 elevation. Linkage analysis indicated that different chromosomes were involved in generating TSHR antibodies and serum T4 before and after immunization. TBI activity was linked in part with major histocompatibility (MHC) genes on chromosome 17 (Chr 17) but induced Graves' disease involved non-MHC genes (Chr 19 and 10). The Chr 10 locus is close to the Trhde gene that encodes TSH-releasing hormone degrading enzyme. Expression of Trhde is controlled by thyroid hormones and linkage with a thyroid function-related gene is intriguing. Our data, the first genome scan in murine Graves' disease, provides insight into the role of MHC and non-MHC genes in human and murine Graves' disease. Finally, our study demonstrates the potential of recombinant inbred mice for discriminating between immune-response genes and thyroid function susceptibility genes in Graves' disease.     

Effects of amiodarone and desethylamiodarone on pituitary deiodinase activity and thyrotropin secretion in the rat

The effect of acute administration of amiodarone, its major metabolite desethylamiodarone and iodine in an amount equal to that contained in amiodarone on serum thyroid hormone and thyrotropin (TSH) concentrations and hepatic and pituitary 5' deiodination of thyroxine (T4) in the euthyroid and hypothyroid rat was evaluated. Amiodarone, desethylamiodarone and iodine all caused a decrease in serum T4 and triiodothyronine (T3) concentrations in euthyroid rats, while serum TSH concentrations and pituitary and hepatic 5' deiodinase activities were decreased only in the amiodarone and desethylamiodarone-treated animals. Serum TSH was increased in the iodine treated rats. Amiodarone, but not iodine, decreased serum T3 and TSH concentrations and pituitary and hepatic 5' deiodinase activities in hypothyroid rats. Inhibition of hepatic 5' deiodinase activity was also observed by the addition of amiodarone in vitro in the absence of dithiothreitol (DTT) but not in the presence of DTT. The decrease in the serum T4 concentration observed with amiodarone and desethylamiodarone administration is probably secondary to the inhibitory effect of iodine released from the drugs on thyroidal T4 synthesis and secretion. Iodine inhibition of thyroidal T3 synthesis and secretion, decreased T4 substrate for a peripheral generation of T3 and inhibition of T4 to T3 conversion all contribute to the decrease in serum T3 observed. The decrease in the serum TSH concentration, despite low serum T4 and T3 concentrations and inhibition of pituitary 5' deiodinase, suggest that amiodarone may function as a thyroid hormone agonist in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cosegregation of Genes on Chromosome 5 with Heart Weight and Blood Pressure in Genetic Hypertension

Genetic factors may be involved in both essential hypertension and cardiac hypertrophy. To identify genes contributing to elevated for blood pressure and cardiac hypertrophy in the spontaneously hypertensive rat (SHR), we performed a cosegregation analysis between blood pressure and heart weight and microsatellite markers for the candidate gene ANF on chromosome 5 in F2 animals obtained by mating SHR with Wistar-Kyoto (WKY) rats. We found evidence for a quantitative trait locus (QTL) determining mean blood pressure on chromosome 5 between atrial natriuretic factor (ANF) and MITR-3893 loci. No evidence for a QTL influencing heart weight was found. We propose that in SHR, blood pressure and heart weight may be independently controlled by different genetic mechanisms and that a gene close to ANF locus on chromosome 5 contributes towards hypertension in these animals.     

Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes

It has been demonstrated that TSH receptors are expressed not only in thyroid gland but also in extrathyroidal tissues. Brown adipose tissue of guinea pig has been reported to express TSH receptor messenger RNA (mRNA), but the physiological roles of TSH receptors in brown adipose tissue have not been understood. We studied the expression and function of TSH receptors in rat brown adipose tissue and cultured rat brown adipocytes. Northern analysis demonstrated the expression of TSH receptor mRNA in rat brown adipose tissue and cultured rat brown adipocytes. TSH receptor mRNA in rat brown adipose tissue was decreased by cold exposure of the rat, and its mRNA in cultured rat brown adipocytes was also decreased by incubation with TSH or (Bu)(2)cAMP. TSH increased the intracellular cAMP concentration in cultured rat brown adipocytes in a dose dependent manner. Type II iodothyronine deiodinase mRNA, its activity, and uncoupling protein-1 mRNA in cultured rat brown adipocytes were significantly increased by incubation with TSH in a dose-dependent manner. These results suggest the expression of functional TSH receptors in brown adipose tissue, which may be involved in regulation of the expression of type II iodothyronine deiodinase and uncoupling protein-1.     

A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine

INTRODUCTION: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. METHODS: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. RESULTS: A SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. CONCLUSIONS: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.     

A major quantitative trait locus on mouse chromosome 3 is involved in disease susceptibility in different colitis models

BACKGROUND & AIMS: Mice with a disrupted gene for the G-protein alpha inhibitory 2 chain ( Gnai2 -/- ) develop a spontaneous colitis resembling human inflammatory bowel disease. Disease expression differs markedly between inbred strains of mice, indicating genetic control of disease susceptibility. We performed a genome-wide screen to localize the chromosomal regions regulating disease expression. METHODS: A total of 284 F2 mice derived from resistant C57BL/6J Gnai2 -/- mice and susceptible C3H/HeN Gnai2 -/- mice were analyzed in a genome-wide screen for colitis susceptibility and severity. RESULTS: A highly significant locus on chromosome 3 (Gpdc1) contributed to colitis susceptibility and severity (likelihood ratio statistics [LRS] = 32.4; LOD score = 7; P < 1.0 x 10(-5)). The peak linkage of this locus at 62 cM colocalizes exactly with a previously identified locus controlling colitis susceptibility in interleukin-10-deficient mice. In addition, evidence for linkage with a locus on chromosome 1 (Gpdc2 ; LRS = 19.7; LOD = 4.3) was found, and the 2 loci interacted epistatically (combined LRS = 68.2). A third locus (Gpdc3) was found on chromosome 9 and this locus interacted epistatically with a locus on chromosome 7, which by itself did not have an effect on the trait. CONCLUSIONS: The identification of a major locus on chromosome 3 that controls susceptibility to spontaneous colitis in 2 different gene-knockout models indicates that this locus harbors a gene(s) that plays a key role in maintaining mucosal homeostasis. Identification of this gene(s) may contribute to further understanding of the mechanisms underlying human inflammatory bowel disease.     

Fine mapping of Lvm1: a quantitative trait locus controlling heart size independently of blood pressure

We have previously reported a quantitative trait locus (QTL) on rat chromosome 2 that influences heart size independently of blood pressure (Left Ventricular Mass Locus 1; Lvm1). The recent release of the rat genome sequence allowed us to retest and refine this relatively broad QTL with a view to identifying within it candidate genes worthy of structural investigation. We sought to achieve this 'fine mapping' by increasing the marker density within the interval and undertaking a linkage analysis in a previously defined population of F2 hybrids generated from inbred spontaneously hypertensive rats (SHR) of the Okamoto strain and Fischer rat (F344) progenitors. We were able to reconfirm and resolve Lvm1 from its original width of approximately 45 to 15 cM. By reference to the ENSEBL rat genome data bank, we identified within Lvm1 27 known genes, 109 predicted genes and 7 pseudogenes. Of the known genes, candidates include potential regulators of cardiac growth, a sodium channel and calcium channel as well as the fibroblast growth factor 2 gene. Located nearby the Lvm1 locus was the gene for the angiotensin Type 1B receptor. Given the evidence that the ligand for the angiotensin Type 1B receptor-angiotensin II-is a potent cardiotroph, we also consider this gene a potential candidate. The identification of the precise allelic variant(s) within Lvm1 involved in the control of pressure-independent cardiac growth awaits further molecular studies.     

Selenium and the control of thyroid hormone metabolism.

Thyroid hormone synthesis, metabolism and action require adequate availability of the essential trace elements iodine and selenium, which affect homeostasis of thyroid hormone-dependent metabolic pathways. The three selenocysteine-containing iodothyronine deiodinases constitute a novel gene family. Selenium is retained and deiodinase expression is maintained at almost normal levels in the thyroid gland, the brain and several other endocrine tissues during selenium deficiency, thus guaranteeing adequate local and systemic levels of the active thyroid hormone T(3). Due to their low tissue concentrations and their mRNA SECIS elements deiodinases rank high in the cellular and tissue-specific hierarchy of selenium distribution among various selenoproteins. While systemic selenium status and expression of abundant selenoproteins (glutathione peroxidase or selenoprotein P) is already impaired in patients with cancer, disturbed gastrointestinal resorption, unbalanced nutrition or patients requiring intensive care treatment, selenium-dependent deiodinase function might still be adequate. However, disease-associated alterations in proinflammatory cytokines, growth factors, hormones and pharmaceuticals modulate deiodinase isoenzyme expression independent from altered selenium status and might thus pretend causal relationships between systemic selenium status and altered thyroid hormone metabolism. Limited or inadequate supply of both trace elements, iodine and selenium, leads to complex rearrangements of thyroid hormone metabolism enabling adaptation to unfavorable conditions.     

Pendred syndrome in two Galician families: insights into clinical phenotypes through cellular, genetic, and molecular studies

CONTEXT: We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter. OBJECTIVE: Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes. INTERVENTIONS: Interventions included extraction of DNA and of thyroid tissue. PATIENTS: Propositi and 10 members of the two families participated in the study. MAIN OUTCOME MEASURES: Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416-1G-->A effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics. RESULTS: Proposita A was heterozygous for c.578C-->T and c.279delT, presented with goiter, and had normal TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416-1G-->A; some deaf relatives were homozygous for c.416-1G-->A but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention. CONCLUSIONS: c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416-1G-->A was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.     

Resistance to thyrotropin

Resistance to TSH is a syndrome of reduced sensitivity to a biologically active TSH molecule. Subjects have elevated TSH levels but no goiter. However, thyroid hormone concentration may vary from normal to very high, depending on the severity of the resistance. Individuals with very high TSH, low T4 and hypoplastic thyroid glands can be mistakenly diagnosed as having primary hypothyroidism due to a defective development of the thyroid gland. Those with normal or slightly decreased T4 can be misdiagnosed as having central hypothyroidism especially if their serum TSH concentration is only slightly elevated. Mutations in the TSH receptor (TSHr) gene have been reported in 16 families with homozygous or compound heterozygous inheritance. The mutant TSHrs show reduced or no function due to either altered ligand binding or defect in membrane targeting. Some individuals, heretozygous for a TSHr gene mutation can present mild resistance to TSH manifesting as euthyroidism with slight hyperthyrotropinemia. A larger proportion of families express the phenotype of resistance to TSH in the absence of a TSHr defect. In many the inheritance is dominant and the genetic cause has not been yet determined.     

甲状腺特异性转录因子对甲状腺功能的调控

甲状腺特异性转录因子是调控甲状腺功能的小分子蛋白,包括甲状腺转录因子(TTF)-1、双链复合蛋白(Pax)-8和TTF-2。生理状态下,促甲状腺激素、胰岛素和胰岛素样生长因子-1通过对TTF-1、TTF-2和Pax-8的表达及活性的调节,上调钠碘同向转运体、甲状腺过氧化物酶、甲状腺球蛋白、促甲状腺激素受体的表达,调节甲状腺功能。Pax-8和TTF-1也可使主要组织相容性复合物Ⅰ表达下调,使甲状腺可以耐受自身激素合成过程中增加的基因产物。TTF-1也可影响人类各组织中5′脱碘酶2型以及甲状腺滤泡旁细胞(C细胞)和甲状旁腺细胞中钙离子转运相关基因的表达。