Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Background Strain C57BL/6 Donor Strain 129P2 via E14TG2a ES cell line Generation N1F3pN1   Donating Investigator Douglas Forrest,   National Institutes of Health

Description
The Thra gene encodes the T3 receptor TRa1 (alpha 1) and a non-T3 bindng product TRa2 (alpha 2), generated by alternative splicing in the C-terminal region. This Thra mutant is deleted for the T3 receptor TRa1 (ALPHA ONE) but retains TRa2. These mutants have an average heart rate 20% lower than that of control animals, prolonged QT_end and QRS durations, body temperatures 0.5 degrees C lower than that of control animals. A mild hypothyrodism is present but is restricted to males.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Thra^tm1Ven/Thra^tm1Ven

        involves: 129P2/OlaHsd * BALB/c

• endocrine/exocrine gland phenotype
• decreased activity of thyroid (MGI Ref ID J:45675)
  • mutant male mice had lower levels of free T4 than control animals
  • no significant differences were found between the female mutant homozygous mice and control
  • the T3 level were normal in all mice
  • the thyroid glands of mutant mice are normal histologically and no goitre has been detected during 18 month observation
• cardiovascular system phenotype
• decreased heart rate (MGI Ref ID J:45675)
  • mutant mice have a lower mean heart rate
  • daily injection of T3 resulted in an increase in heart rate but failed to reach the same heart rate as the control group
• prolonged QT interval (MGI Ref ID J:45675)
  • mutant mice have prolonged QRS- and QTend-interval
  • the QTend duration is markedly prolonged in mutant mice suggesting slow ventricular repolarization
• homeostasis/metabolism phenotype
• decreased body temperature (MGI Ref ID J:45675)
  • 24 h mean body temperature, recorded by the telemetry system, is 0.5 degree C lower in the mutant than the controls
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype (MGI Ref ID J:103702)
  • homozygotes show no significant incidence of audiogenic seizure susceptibility above the 27% incidence noted in background-matched wild-type mice
• hearing/vestibular/ear phenotype
• *normal* hearing/vestibular/ear phenotype (MGI Ref ID J:48666)
  • at 2-3 months of age, homozygotes exhibit normal auditory-evoked brainstem response (ABR) thresholds for click, 8-, 16-, and 32-kHz frequency stimuli
  • in accord with normal ABRs, mutant IHCs show normal developmental expression of the fast-activating potassium current I_K,f at the onset of hearing, indicating normal IHC physiology
• abnormal cochlear outer hair cell morphology (MGI Ref ID J:111711)
  • despite lack of evidence for a role in hearing, Thra appears to be involved in the final differentiation of cochlear OHCs, as shown by studies of KCNQ4 and prestin protein expression under conditions of goitrogen-induced hypothyroidism
• nervous system phenotype
• abnormal cochlear outer hair cell morphology (MGI Ref ID J:111711)
  • despite lack of evidence for a role in hearing, Thra appears to be involved in the final differentiation of cochlear OHCs, as shown by studies of KCNQ4 and prestin protein expression under conditions of goitrogen-induced hypothyroidism

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Thra^tm1Ven related

Cardiovascular Research
Heart Abnormalities

Internal/Organ Research
Heart Abnormalities

Metabolism Research
Low Body Temperature

Genes & Alleles

Gene & Allele Information

Allele Symbol		Thratm1Ven
Allele Name		targeted mutation 1, Bjorn Vennstrom
Allele Type		Targeted (knock-out)
Common Name(s)		TRalpha1 -;
Mutation Made By		Bjorn Vennstrom,   Karolinska Institute
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Thra, thyroid hormone receptor alpha
Chromosome		11
Gene Common Name(s)		6430529J03Rik; AR7; AW259572; EAR7; ERB-T-1; ERBA; ERBA1; Erba; MGC000261; MGC43240; NR1A1; RIKEN cDNA 6430529J03 gene; Rev-Erb A(alpha)-related receptor; Rvr; T3R[a]; T3Ralpha; THRA1; THRA2; TR alpha 1; TR alpha 2; Thra1; Thra2; avian erythroblastosis oncogene A; c-ERBA-1; c-erbAalpha; expressed sequence AW259572; thyroid hormone receptor alpha 1; thyroid hormone receptor alpha 2;
Molecular Note		A gene targeting construct was designed to disrupt the alpha1 isoform, while maintaining the integrity of the alpha2 isoform, as well as the of the orphan hormone receptor rev-erbAalpha that is transcribed on the opposite strand. RT-PCR was used to confirm these results. [MGI Ref ID J:45675]

Genotyping

Genotyping Information

Genotyping Protocols

Thra^tm1Ven, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Wikstrom L; Johansson C; Salto C; Barlow C; Campos Barros A; Baas F; Forrest D; Thoren P; Vennstrom B. 1998. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 17(2):455-61. [PubMed: 9430637]  [MGI Ref ID J:45675]

Additional References

Salto C; Kindblom JM; Johansson C; Wang Z; Gullberg H; Nordstrom K; Mansen A; Ohlsson C; Thoren P; Forrest D; Vennstrom B. 2001. Ablation of TRalpha2 and a Concomitant Overexpression of alpha1 Yields a Mixed Hypo- and Hyperthyroid Phenotype in Mice. Mol Endocrinol 15(12):2115-28. [PubMed: 11731613]  [MGI Ref ID J:72959]

Thra^tm1Ven related

Amma LL; Campos-Barros A; Wang Z; Vennstrom B; Forrest D. 2001. Distinct Tissue-Specific Roles for Thyroid Hormone Receptors beta and alpha1 in Regulation of Type 1 Deiodinase Expression. Mol Endocrinol 15(3):467-75. [PubMed: 11222747]  [MGI Ref ID J:67946]

Billon N; Jolicoeur C; Tokumoto Y; Vennstrom B; Raff M. 2002. Normal timing of oligodendrocyte development depends on thyroid hormone receptor alpha 1 (TRalpha1). EMBO J 21(23):6452-60. [PubMed: 12456652]  [MGI Ref ID J:110812]

Calza L; Forrest D; Vennstrom B; Hokfelt T. 2000. Expression of peptides and other neurochemical markers in hypothalamus and olfactory bulb of mice devoid of all known thyroid hormone receptors. Neuroscience 101(4):1001-12. [PubMed: 11113349]  [MGI Ref ID J:118024]

Dellovade TL; Chan J; Vennstrom B; Forrest D; Pfaff DW. 2000. The two thyroid hormone receptor genes have opposite effects on estrogen-stimulated sex behaviors. Nat Neurosci 3(5):472-5. [PubMed: 10769387]  [MGI Ref ID J:61839]

Furumoto H; Ying H; Chandramouli GV; Zhao L; Walker RL; Meltzer PS; Willingham MC; Cheng SY. 2005. An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis. Mol Cell Biol 25(1):124-35. [PubMed: 15601836]  [MGI Ref ID J:95391]

Golozoubova V; Gullberg H; Matthias A; Cannon B; Vennstrom B; Nedergaard J. 2004. Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors. Mol Endocrinol 18(2):384-401. [PubMed: 14630998]  [MGI Ref ID J:87747]

Gothe S; Wang Z; Ng L; Kindblom JM; Barros AC; Ohlsson C; Vennstrom B; Forrest D. 1999. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 13(10):1329-41. [PubMed: 10346821]  [MGI Ref ID J:55414]

Grover GJ; Mellstrom K; Ye L; Malm J; Li YL; Bladh LG; Sleph PG; Smith MA; George R; Vennstrom B; Mookhtiar K; Horvath R; Speelman J; Egan D; Baxter JD. 2003. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A 100(17):10067-72. [PubMed: 12888625]  [MGI Ref ID J:85167]

Guadano-Ferraz A; Benavides-Piccione R; Venero C; Lancha C; Vennstrom B; Sandi C; DeFelipe J; Bernal J. 2003. Lack of thyroid hormone receptor alpha1 is associated with selective alterations in behavior and hippocampal circuits. Mol Psychiatry 8(1):30-8. [PubMed: 12556906]  [MGI Ref ID J:103801]

Gullberg H; Rudling M; Forrest D; Angelin B; Vennstrom B. 2000. Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol. Mol Endocrinol 14(11):1739-49. [PubMed: 11075809]  [MGI Ref ID J:125475]

Johansson C; Gothe S; Forrest D; Vennstrom B; Thoren P. 1999. Cardiovascular phenotype and temperature control in mice lacking thyroid hormone receptor-beta or both alpha1 and beta. Am J Physiol 276(6 Pt 2):H2006-12. [PubMed: 10362681]  [MGI Ref ID J:55864]

Johansson C; Lannergren J; Lunde PK; Vennstrom B; Thoren P; Westerblad H. 2000. Isometric force and endurance in soleus muscle of thyroid hormone receptor-alpha(1)- or -beta-deficient mice. Am J Physiol Regul Integr Comp Physiol 278(3):R598-603. [PubMed: 10712278]  [MGI Ref ID J:61289]

Johansson C; Lunde PK; Gothe S; Lannergren J; Westerblad H. 2003. Isometric force and endurance in skeletal muscle of mice devoid of all known thyroid hormone receptors. J Physiol 547(Pt 3):789-96. [PubMed: 12562961]  [MGI Ref ID J:105508]

Johnson KR; Zheng QY; Noben-Trauth K. 2006. Strain background effects and genetic modifiers of hearing in mice. Brain Res 1091(1):79-88. [PubMed: 16579977]  [MGI Ref ID J:110459]

Kindblom JM; Gevers EF; Skrtic SM; Lindberg MK; Gothe S; Tornell J; Vennstrom B; Ohlsson C. 2005. Increased adipogenesis in bone marrow but decreased bone mineral density in mice devoid of thyroid hormone receptors. Bone 36(4):607-16. [PubMed: 15780976]  [MGI Ref ID J:98068]

Kindblom JM; Kindblom JM; Gothe S; Forrest D; Tornell J; Tornell J; Vennstrom B; Ohlsson C. 2001. GH substitution reverses the growth phenotype but not the defective ossification in thyroid hormone receptor alpha1-/-beta-/- mice. J Endocrinol 171(1):15-22. [PubMed: 11572786]  [MGI Ref ID J:72045]

Mansen A; Yu F; Forrest D; Larsson L; Vennstrom B. 2001. TRs have common and isoform-specific functions in regulation of the cardiac myosin heavy chain genes. Mol Endocrinol 15(12):2106-14. [PubMed: 11731612]  [MGI Ref ID J:72960]

Mittag J; Friedrichsen S; Heuer H; Polsfuss S; Visser TJ; Bauer K. 2005. Athyroid Pax8-/- mice cannot be rescued by the inactivation of thyroid hormone receptor alpha1. Endocrinology 146(7):3179-84. [PubMed: 15802493]  [MGI Ref ID J:126169]

Morte B; Manzano J; Scanlan TS; Vennstrom B; Bernal J. 2004. Aberrant maturation of astrocytes in thyroid hormone receptor alpha 1 knockout mice reveals an interplay between thyroid hormone receptor isoforms. Endocrinology 145(3):1386-91. [PubMed: 14630717]  [MGI Ref ID J:105582]

Ng L; Pedraza PE; Faris JS; Vennstrom B; Curran T; Morreale de Escobar G; Forrest D. 2001. Audiogenic seizure susceptibility in thyroid hormone receptor beta-deficient mice. Neuroreport 12(11):2359-62. [PubMed: 11496110]  [MGI Ref ID J:103702]

Rusch A; Erway LC; Oliver D; Vennstrom B; Forrest D. 1998. Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing. Proc Natl Acad Sci U S A 95(26):15758-62. [PubMed: 9861043]  [MGI Ref ID J:118178]

Rusch A; Erway LC; Vennstrom B; Forrest D. 1998. Thyroid hormone receptor Beta is involved in developmental maturation of inner hair cell ionic conductances Hered Deaf News 15:51.  [MGI Ref ID J:48666]

Rusch A; Ng L; Goodyear R; Oliver D; Lisoukov I; Vennstrom B; Richardson G; Kelley MW; Forrest D. 2001. Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors. J Neurosci 21(24):9792-800. [PubMed: 11739587]  [MGI Ref ID J:73382]

Tinnikov A; Nordstrom K; Thoren P; Kindblom JM; Malin S; Rozell B; Adams M; Rajanayagam O; Pettersson S; Ohlsson C; Chatterjee K; Vennstrom B. 2002. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. EMBO J 21(19):5079-87. [PubMed: 12356724]  [MGI Ref ID J:100290]

Winter H; Braig C; Zimmermann U; Geisler HS; Franzer JT; Weber T; Ley M; Engel J; Knirsch M; Bauer K; Christ S; Walsh EJ; McGee J; Kopschall I; Rohbock K; Knipper M. 2006. Thyroid hormone receptors TRalpha1 and TRbeta differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells. J Cell Sci 119(Pt 14):2975-84. [PubMed: 16803873]  [MGI Ref ID J:111711]

Wistuba J; Mittag J; Luetjens CM; Cooper TG; Yeung CH; Nieschlag E; Bauer K. 2007. Male congenital hypothyroid Pax8-/- mice are infertile despite adequate treatment with thyroid hormone. J Endocrinol 192(1):99-109. [PubMed: 17210747]  [MGI Ref ID J:117324]

Yu F; Gothe S; Wikstrom L; Forrest D; Vennstrom B; Larsson L. 2000. Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles. Am J Physiol Regul Integr Comp Physiol 278(6):R1545-54. [PubMed: 10848522]  [MGI Ref ID J:63071]

Zhang XY; Kaneshige M; Kamiya Y; Kaneshige K; McPhie P; Cheng SY. 2002. Differential expression of thyroid hormone receptor isoforms dictates the dominant negative activity of mutant Beta receptor. Mol Endocrinol 16(9):2077-92. [PubMed: 12198244]  [MGI Ref ID J:78703]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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