migration but hypothyroidism in mutant mice Mice with all possible genotypes were recovered at Mendelian frequency at birth, suggesting that Kif3a deletion in Pax8-expressing cells is not embryonically lethal. Nevertheless, at weaning around 3 weeks of age
Eva D'Amico, Stéphanie Gayral, Claude Massart, Jacqueline Van Sande, Jeremy F Reiter, Jacques E Dumont, Bernard Robaye and Stéphane Schurmans
Ariane Zamoner, Kátia Padilha Barreto, Danilo Wilhelm Filho, Fabíola Sell, Viviane Mara Woehl, Fátima Costa Rodrigues Guma, Regina Pessoa-Pureur and Fátima Regina Mena Barreto Silva
evidence that THs regulate Sertoli cell proliferation and differentiation in the neonatal testis. Accordingly, alterations in thyroid activity are frequently associated with changes in male reproductive functions, since hypothyroidism is associated with a
C Féart, J Vallortigara, D Higueret, B Gatta, A Tabarin, V Enderlin, P Higueret and V Pallet
- and hypothyroidism induce considerable consequences in children and adults. For example, children born with congenital hypothyroidism who lack thyroid hormones during a circumscribed period of early development are at risk of brain damage and mental
Sogol Gachkar, Sebastian Nock, Cathleen Geissler, Rebecca Oelkrug, Kornelia Johann, Julia Resch, Awahan Rahman, Anders Arner, Henriette Kirchner and Jens Mittag
hypothyroid individuals ( Klein & Ojamaa 2001 ). In addition to its direct effects on the heart ( Dillmann 2010 ), TH also affects the vascular system. It was for instance reported that hyper- as well as hypothyroidism are associated with increased arterial
Isabel Castro, Leah Quisenberry, Rosa-Maria Calvo, Maria-Jesus Obregon and Joaquin Lado-Abeal
increased probability of death ( Slag et al . 1981 ). NTIS results from a central hypothyroidism together with tissue-specific changes resembling consumptive hypothyroidism and reduced sensitivity to TH action. Studies on humans have shown that central
JM Weitzel, S Hamann, M Jauk, M Lacey, A Filbry, C Radtke, KA Iwen, S Kutz, A Harneit, PM Lizardi and HJ Seitz
Thyroid hormone (T3) is essential for normal development, differentiation and metabolic balance. We have performed DNA microarray experiments using hepatic RNA from hypothyroid and T3-treated hypothyroid rats in order to characterize T3-induced gene expression patterns after various time points (6, 24 and 48 h after the administration of the hormone). Sixty-two of 4608 different genes displayed a reproducible T3-response, and cluster analysis divided these differentially regulated genes into six expression patterns. Thirty-six genes were not significantly regulated within the first 24 h. Transient transfection experiments of eight late-induced gene promoters failed to detect a thyroid hormone response element within their regulatory elements, suggesting an indirect activation mechanism(s). In search for an intermediate factor of T3 action, we examined whether various rather ubiquitous transcription factors, peroxisome proliferator-activated receptors (PPARs) and coactivators of the PPARgamma coactivator 1 family (PGC-1) are regulated by T3. Only PPARgamma and PERC/PGC-1beta exhibit a significant T3-response within the first 6 h after treatment, identifying these factors as candidate components for mediating the late-induced expression pattern. Regulation of early-induced genes within the first 6 h after administration of T3 on transcript levels correlates with altered protein levels after 24 and 48 h in vivo.
M Baryshev, E Sargsyan, G Wallin, A Lejnieks, S Furudate, A Hishinuma and S Mkrtchian
The unfolded protein response (UPR) is an intracellular signaling pathway that regulates the protein folding and processing capacity of the endoplasmic reticulum (ER). The UPR is induced by the pharmacological agents that perturb ER functions but is also activated upon excessive accumulation of the mutant secretory proteins that are unable to attain correct three-dimensional structure and are thus retained in the ER. Such defects in intracellular protein transport underlie the development of a number of phenotypically diverse inherited pathologies, termed endoplasmic reticulum storage diseases (ERSD). We have studied UPR development in two similar ERSDs, human congenital goiter caused by the C1264R and C1996S mutations in the thyroglobulin (Tg) gene and non-goitrous congenital hypothyroidism in rdw dwarf rats determined by the G2320R Tg mutation. In both cases, these mutations rendered Tg incapable of leaving the ER. A major ER chaperone immunoglobulin-binding protein (BiP), and a novel putative escort chaperone endoplasmic reticulum protein 29 KDa (ERp29) were found to be associated with Tg, which might be interpreted as the contribution of the quality control machinery to the previously shown retention of Tg in the ER. We have extended our earlier observations of ER chaperone induction with the identification of the additional ER (ERp29, ERp72, calreticulin, protein disulfide isomerase (PDI)), cytoplasmic (heat shock protein (HSP)70, HSP90) and mitochondrial (mtHSP70) upregulated chaperones and folding enzymes. Activation of the transcriptional arm of UPR, as judged by the appearance of the spliced (active) form of X-box binding protein (XBP1) and processed activating transcription factor 6 (ATF6) transcription factors was suggested to contribute to the overexpression of the ER chaperones. The processing of ATF6 was observed in both human and rat tissues with Tg mutations. Whereas, in human tissues, weak splicing of XBP1 mRNA was detected only in the C1264R mutant, all rat thyroids including wild-type contained significant amounts of the spliced form of XBP1 as opposed to human liver and rat brain tissues, implying the existence of a previously unknown tissue-specific regulation of XBP1 processing.
A. J. Pickles, N. Peers, W. R. Robertson and A. Lambert
The microheterogeneity of pituitary thyroid-stimulating hormone (TSH) is dependent on variations in the hormone's carbohydrate moieties. In this study, changes in the pattern of heterogeneity have been assessed by chromatofocusing, which separates the isospecies on the basis of their isoelectric points (pI). Rats (n = 6 per group) were either untreated or rendered hypo- or hyperthyroid by including in the drinking water either propylthiouracil (0·05% for 8 weeks) or thyroxine (T4; 4 mg/l for 6 weeks) before they were killed at 16 weeks. On autopsy, serum TSH and total T4 were (means±s.e.m.): 2±0·3 μg TSH/l and 64±5 nmol T4/l (control); <1 μg TSH/1 and 133±6 nmol T4/l (hyperthyroid); 58±6 μg TSH/1 and 32±6 nmol T4/l (hypothyroid). The pituitaries were individually homogenized and the TSH isoforms separated by chromatofocusing over a pH range of 7–4. Fractions were assayed for TSH by radioimmunoassay. TSH from the control group was distributed into seven major peaks with pI values of (means ±s.e.m., n=6) 6·9±0·1, 6·6±0·1, 6·2±0·1, 5·8±0·1, 5·5±0·1, 5·2±0·1 and 4·8±0·1; 7±3% of the TSH had a pI of <40. Six peaks of TSH were conserved in the hypothyroid group (with pI values of 6·8±0·1, 6·5±0·1, 6·2±0·1, 5·8±0·1, 5·4±0·1 and 5·2±0·1), and 11±4% of the hormone had a pI of <40. In contrast to the other two groups, only one major peak (with a pI of 5·8±0·1) was detected in the pituitaries from the hyperthyroid group; 13 ± 5% of the TSH had a pI of <40. In the pH range of 5·5– 60, the per cent distribution of TSH was 58±15 (hyperthyroid) compared with 17 ± 3 (hypothyroid) and 22±3 (euthyroid). Above pH 6, only 25±13% of the TSH (hyperthyroid) was present compared with 46±5% (hypothyroid) and 45±5% (euthyroid). Below pH 5·5, the per cent distribution of TSH was 19±5 (hyperthyroid), 37±5 (hypothyroid) and 35±3 (euthyroid). In conclusion, both hyper- and hypothyroidism are associated with changes in the composition of pituitary TSH. This change was most marked in the hyperthyroid group, where there was a selective loss of several isoforms of TSH.
MS Wagner, R Morimoto, JM Dora, A Benneman, R Pavan and AL Maia
In the present study we show the expression profiles of both type 1 and type 2 iodothyronine deiodinases (D1 and D2) in a wide spectrum of mouse tIssues, and D2 regulation by thyroid status. A characteristic tIssue-specific expression for each isoform was observed. D2 transcripts were detected in most tIssues with variable levels of expression. The observed D2 mRNA tIssue distribution was similar to that described in rats and is in agreement with the view of different patterns of expression between rodents and humans. However, it is interesting to note that despite the low levels of D2 transcripts in mouse heart and testis in the euthyroid state, the induction of hypothyroidism caused a significant increase in D2 activity in these tIssues. Similar results were also obtained in adult rats. These results suggest a previously unrecognized role for type 2 deiodinase in controlling intracellular triiodothyronine levels in rodent heart and testis during states of thyroid hormone deficiency.
K Alexander Iwen, Rebecca Oelkrug and Georg Brabant
summarise the effects of (i) cold or heat exposure and (ii) fasting or fed states on metabolic processes. Finally, the disruption of these fine-tuned mechanisms by hyperthyroidism and hypothyroidism will be addressed. Components of thermoregulation