scholarly journals Targeted Disruption of the Type 1 Selenodeiodinase Gene (Dio1) Results in Marked Changes in Thyroid Hormone Economy in Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 580-589 ◽  
Author(s):  
Mark J. Schneider ◽  
Steven N. Fiering ◽  
B. Thai ◽  
Sing-yung Wu ◽  
Emily St. Germain ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Normal Serum ◽  
Reproductive Capacity ◽  
Fecal Excretion ◽  
Wild Type ◽  
Targeted Disruption ◽  
Normal Thyroid Function ◽  
Serum T3

The type 1 deiodinase (D1) is thought to be an important source of T3 in the euthyroid state. To explore the role of the D1 in thyroid hormone economy, a D1-deficient mouse (D1KO) was made by targeted disruption of the Dio1 gene. The general health and reproductive capacity of the D1KO mouse were seemingly unimpaired. In serum, levels of T4 and rT3 were elevated, whereas those of TSH and T3 were unchanged, as were several indices of peripheral thyroid status. It thus appears that the D1 is not essential for the maintenance of a normal serum T3 level in euthyroid mice. However, D1 deficiency resulted in marked changes in the metabolism and excretion of iodothyronines. Fecal excretion of endogenous iodothyronines was greatly increased. Furthermore, when compared with both wild-type and D2-deficient mice, fecal excretion of [125I]iodothyronines was greatly increased in D1KO mice during the 48 h after injection of [125I]T4 or [125I]T3, whereas urinary excretion of [125I]iodide was markedly diminished. From these data it was estimated that a majority of the iodide generated by the D1 was derived from substrates other than T4. Treatment with T3 resulted in a significantly higher serum T3 level and a greater degree of hyperthyroidism in D1KO mice than in wild-type mice. We conclude that, although the D1 is of questionable importance to the wellbeing of the euthyroid mouse, it may play a major role in limiting the detrimental effects of conditions that alter normal thyroid function, including hyperthyroidism and iodine deficiency.

scholarly journals Excretion of Wild-Type and Vaccine-Derived Poliovirus in the Feces of Poliovirus Receptor-Transgenic Mice

2003 ◽  
Vol 77 (11) ◽  
pp. 6541-6545 ◽  
Author(s):  
Hein J. Boot ◽  
Daniella T. J. Kasteel ◽  
Anne-Marie Buisman ◽  
Tjeerd G. Kimman
Keyword(s):  
Transgenic Mice ◽  
Oral Polio Vaccine ◽  
Fecal Excretion ◽  
Wild Type ◽  
Genetic Determinants ◽  
Poliovirus Type ◽  
Oral Transmission ◽  
Polio Vaccine ◽  
Poliovirus Receptor

ABSTRACT The emergence of circulating vaccine-derived poliovirus (cVDPV) strains in suboptimally vaccinated populations is a serious threat to the global poliovirus eradication. The genetic determinants for the transmissibility phenotype of polioviruses, and in particularly of cVDPV strains, are currently unknown. Here we describe the fecal excretion of wild-type poliovirus, oral polio vaccine, and cVDPV (Hispaniola) strains after intraperitoneal injection in poliovirus receptor-transgenic mice. Both the pattern and the level of fecal excretion of the cVDPV strains resemble those of wild-type poliovirus type 1. In contrast, very little poliovirus was present in the feces after oral polio vaccine administration. This mouse model will be helpful in elucidating the genetic determinants for the high fecal-oral transmission phenotype of cVDPV strains.

scholarly journals Poliomyelitis surveillance in England and Wales, 1969–1975

1978 ◽  
Vol 80 (1) ◽  
pp. 155-167 ◽  
Author(s):  
J. W. G. Smith ◽  
P. J. Wherry
Keyword(s):  
Reproductive Capacity ◽  
Paralytic Poliomyelitis ◽  
Test Results ◽  
Wild Type ◽  
England And Wales ◽  
Marker Test ◽  
Type 3 ◽  
Temperature Test

SUMMARYPoliomyelitis continued to be a rare disease in England and Wales in the period 1969–75. Only 31 paralytic and 44 cases of possible non-paralytic poliomyelitis were recorded during the 7 years.Of the 31 paralytic cases approximately one third were vaccine-associated; 3 were patients who had recently received oral poliovaccine and 7 had been in contact with a vaccinated person. Five of these 7 patients were parents of recently vaccinated children. The rate of vaccine-associated poliomyelitis was estimated in recipients to be 0·2 and in contacts 0·4 per million doses of vaccine given.Marker test results were reported on 555 strains of poliomyelitis virus isolated during 1969–75, using the reproductive capacity temperature test. Forty-eight (8·6%) resembled wild virus in this property, 15 strains being type 1, 8 type 2 and 25 type 3. Most of these isolations of apparently wild virus were from excreters with no symptoms of poliomyelitis, although 3 of the 15 type 1 strains were from patients with paralytic poliomyelitis and 3 from possible cases of non-paralytic poliomyelitis. None of the 8 apparently wild type 2 viruses was from a case of paralytic illness and only 1 of the 39 type 3 strains.Eleven of the 31 paralytic cases were in patients in whom the infection was likely to have been acquired abroad.

scholarly journals Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

1998 ◽  
Vol 5 (4) ◽  
pp. 289-301 ◽  
Author(s):  
Michael P. McDonald ◽  
Rosemary Wong ◽  
Gregory Goldstein ◽  
Bruce Weintraub ◽  
Sheue-yann Cheng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Sustained Attention ◽  
Receptor Gene ◽  
Operant Chamber ◽  
Elevated Serum ◽  
Vigilance Task ◽  
Serum Levels ◽  
Wild Type ◽  
Wild Type Littermate

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β(TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRβ gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRβ gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.

scholarly journals The Antiviral Efficacy of the Murine Alpha-1 Interferon Transgene against Ocular Herpes Simplex Virus Type 1 Requires the Presence of CD4+, α/β T-Cell Receptor-Positive T Lymphocytes with the Capacity To Produce Gamma Interferon

2002 ◽  
Vol 76 (18) ◽  
pp. 9398-9406 ◽  
Author(s):  
Daniel J. J. Carr ◽  
Sansanee Noisakran
Keyword(s):  
T Cell ◽  
Plasmid Vector ◽  
Cell Receptor ◽  
Wild Type ◽  
Targeted Disruption ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Deficient Mice ◽  
Hsv 1

ABSTRACT Alpha/beta interferons (IFN-α/βs) are known to antagonize herpes simplex virus type 1 (HSV-1) infection by directly blocking viral replication and promoting additional innate and adaptive, antiviral immune responses. To further define the relationship between the adaptive immune response and IFN-α/β, the protective effect induced following the topical application of plasmid DNA containing the murine IFN-α1 transgene onto the corneas of wild-type and T-cell-deficient mice was evaluated. Mice homozygous for both the T-cell receptor (TCR) β- and δ-targeted mutations expressing no αβ or γδ TCR (αβ/γδ TCR double knockout [dKO]) treated with the IFN-α1 transgene succumbed to ocular HSV-1 infection at a rate similar to that of αβ/γδ TCR dKO mice treated with the plasmid vector DNA. Conversely, mice with targeted disruption of the TCR δ chain and expressing no γδ TCR+ cells treated with the IFN-α1 transgene survived the infection to a greater extent than the plasmid vector-treated counterpart and at a level similar to that of wild-type controls treated with the IFN-α1 transgene. By comparison, mice with targeted disruption of the TCR β chain and expressing no αβ TCR+ cells (αβ TCR knockout [KO]) showed no difference upon treatment with the IFN-α1 transgene or the plasmid vector control, with 0% survival following HSV-1 infection. Adoptively transferring CD4+ but not CD8+ T cells from wild-type but not IFN-γ-deficient mice reestablished the antiviral efficacy of the IFN-α1 transgene in αβ TCR KO mice. Collectively, the results indicate that the protective effect mediated by topical application of a plasmid construct containing the murine IFN-α1 transgene requires the presence of CD4+ T cells capable of IFN-γ synthesis.

scholarly journals Absence of Thyroid Hormone Activation during Development Underlies a Permanent Defect in Adaptive Thermogenesis

2010 ◽  
Vol 31 (4) ◽  
pp. 603-603
Author(s):  
Jessica A. Hall ◽  
Scott Ribich ◽  
Marcelo A. Christoffolete ◽  
Gordana Simovic ◽  
Mayrin Correa-Medina ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Energy Homeostasis ◽  
Cell Model ◽  
Oxidative Capacity ◽  
Normal Serum ◽  
Hormone Signaling ◽  
Expression Of Genes ◽  
Brown Adipose ◽  
Serum T3 ◽  
A Cell

Abstract Type 2 deiodinase (D2), which is highly expressed in brown adipose tissue (BAT), is an enzyme that amplifies thyroid hormone signaling in individual cells. Mice with inactivation of the D2 pathway (D2KO) exhibit dramatically impaired thermogenesis in BAT, leading to hypothermia during cold exposure and a greater susceptibility to diet-induced obesity. This was interpreted as a result of defective acute activation of BAT D2. Here we report that the adult D2KO BAT has a permanent thermogenic defect that stems from impaired embryonic BAT development. D2KO embryos have normal serum T3 but due to lack of D2-generated T3 in BAT, this tissue exhibits decreased expression of genes defining BAT identity [i.e. UCP1, PGC-1α and Dio2 (nonfunctional)], which results in impaired differentiation and oxidative capacity. Coinciding with a reduction of these T3-responsive genes, there is oxidative stress that in a cell model of brown adipogenesis can be linked to decreased insulin signaling and decreased adipogenesis. This discovery highlights the importance of deiodinase-controlled thyroid hormone signaling in BAT development, where it has important metabolic repercussions for energy homeostasis in adulthood.

scholarly journals Interleukin 4 Gene–defective Mice Reconstituted with Wild-type Bone Marrow Fail to Produce Normal Immunoglobulin E Levels

1998 ◽  
Vol 187 (9) ◽  
pp. 1487-1493 ◽  
Author(s):  
Claudia Lange ◽  
Thomas Schüler ◽  
Thomas Blankenstein
Keyword(s):  
Bone Marrow ◽  
Immunoglobulin E ◽  
Serum Levels ◽  
Normal Serum ◽  
Interleukin 4 ◽  
Wild Type ◽  
Normal Threshold ◽  
Adult Mice ◽  
Unidentified Source ◽  
Intrasplenic Injection

The ability to reconstitute interleukin (IL)-4−/− mice with bone marrow of IL-4+/+ mice was investigated. The absence of the IL-4−/− gene in donor or recipient cells did not impair the reconstitution. All immunoglobulin (Ig) subsets occurred at normal serum levels except for IgE and to some extent IgG1. IgE production did not recover in the reconstituted mice over prolonged time. However, these mice were competent for IgE production, because a single intrasplenic injection of IL-4 restored IgE levels, which then remained constant. Wild-type mice reconstituted with wild-type bone marrow constantly had IgE serum levels comparable to untreated animals. In wild-type mice reconstituted with IL-4−/− bone marrow, IgE levels dropped gradually and disappeared by week 12. We make three unrelated but nonetheless important conclusions: (a) (immunoregulation) the tightly regulated IL-4 gene should be expressed constantly in low amounts (and with apparent absence of antigen stimulation) to keep the normal threshold of IgE; (b) (ontogeny of the immune system) an early unidentified source of IL-4 must be postulated which is lost in adult mice; and (c) (bone marrow transfer/gene therapy) under certain circumstances, the genotype of the recipient influences the reconstitution.

scholarly journals Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3682-3695 ◽  
Author(s):  
Barbara M. L. C. Bocco ◽  
João Pedro Werneck-de-Castro ◽  
Kelen C. Oliveira ◽  
Gustavo W. Fernandes ◽  
Tatiana L. Fonseca ◽  
...  
Keyword(s):  
Serum Levels ◽  
Normal Serum ◽  
Phenotype Microarray ◽  
Mrna Levels ◽  
Microarray Gene Expression ◽  
Gene Sets ◽  
Daily Exercise ◽  
Serum T3 ◽  
The Brain

Millions of levothyroxine-treated hypothyroid patients complain of impaired cognition despite normal TSH serum levels. This could reflect abnormalities in the type 2 deiodinase (D2)-mediated T4-to-T3 conversion, given their much greater dependence on the D2 pathway for T3 production. T3 normally reaches the brain directly from the circulation or is produced locally by D2 in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T3 but exhibit anxiety-depression-like behavior as found in open field and elevated plus maze studies and when tested for depression using the tail-suspension and the forced-swimming tests. Remarkably, 4 weeks of daily treadmill exercise sessions eliminated this phenotype. Microarray gene expression profiling of the Astro-D2KO hippocampi identified an enrichment of three gene sets related to inflammation and impoverishment of three gene sets related to mitochondrial function and response to oxidative stress. Despite normal neurogenesis, the Astro-D2KO hippocampi exhibited decreased expression of four of six known to be positively regulated genes by T3, ie, Mbp (∼43%), Mag (∼34%), Hr (∼49%), and Aldh1a1 (∼61%) and increased expression of 3 of 12 genes negatively regulated by T3, ie, Dgkg (∼17%), Syce2 (∼26%), and Col6a1 (∼3-fold) by quantitative real-time PCR. Notably, in Astro-D2KO animals, there was also a reduction in mRNA levels of genes known to be affected in classical animal models of depression, ie, Bdnf (∼18%), Ntf3 (∼43%), Nmdar (∼26%), and GR (∼20%), which were also normalized by daily exercise sessions. These findings suggest that defects in Dio2 expression in the brain could result in mood and behavioral disorders.

scholarly journals Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 315-325 ◽  
Author(s):  
Julia Müller ◽  
Steffen Mayerl ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
Anita Boelen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Elevated Serum ◽  
Normal Serum ◽  
Monocarboxylate Transporter ◽  
Cellular Transport ◽  
Tissue Specific ◽  
Serum T3 ◽  
Serum T4 ◽  
Mct8 Deficiency

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

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