Description

Strain Information

Type Mutant Stock; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Hemizygote x Noncarrier         (Female x Male)   02-APR-11 Species laboratory mouse Generation F?+F6 (21-DEC-12) Generation Definitions   Donating Investigator Jeffery D. Molkentin,   Children's Hospital Medical Center Donating Investigator Eric N Olson,   University of Texas Southwestern Medical

Description
Calcineurin A (Ppp3ca) expression is driven by the cardiomyocyte-specific alpha myosin heavy chain (alpha MHC) promoter in this transgenic strain. Mice develop cardiac hypertrophy that progresses to dilated cardiomyopathy with interstitial fibrosis, congestive heart failure and sudden death between 6 and 12 months of age. This strain may be useful as a model of human heart disease.

Development
The mouse Myh6 (myosin heavy chain, cardiac/alpha) promoter drives expression of the mouse Ppp3ca (protein phosphatase 3, catalytic subunit, alpha isoform; calcineurin A) cDNA. The vector was introduced to FVB oocytes and the strain was maintained through crosses to B6C3F1 hybrid mice by the donating laboratory. This is foundation line 37.

Control Information

	Control
	Noncarrier
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Myh6

012389	B6.Cg-Tg(Myh6-Ppara)404-3Dpk/J
012382	B6.Cg-Tg(Myh6-Ppara)404-4Dpk/J
005657	B6.FVB(129)-Tg(Myh6-cre/Esr1*)1Jmk/J
011038	B6.FVB-Tg(Myh6-cre)2182Mds/J
013781	B6;FVB-Tg(Myh6/NFAT-luc)1Jmol/J
002640	B6;SJL-Tg(Myh6-ADRBK1)27Wjk/J
012383	B6CBA-Tg(Myh6-Ppard)HEDpk/J
002639	B6SJL-Tg(Myh6-ADRBK1)12Wjk/J
002638	B6SJL-Tg(WTbeta2)4Wjk/J
006768	D2.Cg-Tg(Myh6-Zfpm2)1Sho/EiJ
010587	FVB-Tg(Myh6-MEF2A)1Jmol/J
010581	FVB-Tg(Myh6-Map2k1*)1Jmol/J
010582	FVB-Tg(Myh6-Map2k3*)1Jmol/J
010584	FVB-Tg(Myh6-Map2k7)1Jmol/J
010585	FVB-Tg(Myh6-Mapk1)1Jmol/J
010583	FVB-Tg(Myh6-Mapk14*)1Jmol/J
010586	FVB-Tg(Myh6-Mef2c)2Jmol/J
009438	FVB-Tg(Myh6-SOD2,Tyr)3Pne/J
016570	FVB-Tg(Myh6-TRPC3*)6.6Jmol/J
017543	FVB-Tg(Myh6-TRPC6*)1Jmol/J
011037	FVB-Tg(Myh6-cre)2182Mds/J
010588	FVB-Tg(Myh6/NFAT-luc)1Jmol/J
017542	FVB-Tg(Myh6/tetO-ATP2B4)1Jmol/J
016571	FVB-Tg(Myh6/tetO-Gata6)2Jmol/J
014155	FVB-Tg(Myh6/tetO-Itpr1)22.3Jmol/J
014153	FVB-Tg(Myh6/tetO-Itpr2)3.11Jmol/J
012684	FVB-Tg(Myh6/tetO-POSTN)22.1Jmol/J
010580	FVB-Tg(Myh6/tetO-PRKCA*)1Jmk/J
002535	FVB/N-Tg(ANX6)2Agh/J
012459	FVB/N-Tg(Myh6*/tetO-Capn1)L2Gwd/J
008716	FVB/N-Tg(Myh6-AIP/PLN*)46Jded/J
012461	FVB/N-Tg(Myh6-Cast)1Gwd/J
012460	FVB/N-Tg(Myh6-Gnaq)40Gwd/J
012477	STOCK Tg(Myh6*/tetO-GCaMP2)1Mik/J
010579	STOCK Tg(Myh6-Prkca)1Jmk/J
009074	STOCK Tg(Myh6-cre)1Jmk/J
005650	STOCK Tg(Myh6-cre/Esr1*)1Jmk/J
016572	STOCK Tg(Myh6/tetO-Gata4)1Jmol/J

View Strains carrying other alleles of Myh6     (38 strains)

Strains carrying other alleles of Ppp3ca

017331	B6.Cg-Tg(tetO-Ppp3ca*)11255Kndl/J
017332	B6.Cg-Tg(tetO-Ppp3ca*)13967Kndl/J

View Strains carrying other alleles of Ppp3ca     (2 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Tg(Myh6-Ppp3ca)37Eno/0

        involves: FVB

• mortality/aging
• premature death
  • transgenic mice are highly susceptible to sudden death from heart failure   (MGI Ref ID J:93176)
• cardiovascular system phenotype
• cardiac hypertrophy
  • the heart to body weight ratio is increased 2-3 fold as early as P18 with concentric hypertrophy seen, both ventricles and atria are affected   (MGI Ref ID J:93176)
  • cyclosporin A treatment prevented hypertrophy and fibrosis   (MGI Ref ID J:93176)
• cardiac interstitial fibrosis
  • extensive, primarily interstitial fibrosis is seen in the ventricular walls sometimes associated with myofiber degeneration   (MGI Ref ID J:93176)
• dilated heart left ventricle
  • dilation of the ventricles is seen in older transgenic mice   (MGI Ref ID J:93176)
• dilated heart right ventricle
  • dilation of the ventricles is seen in older transgenic mice   (MGI Ref ID J:93176)
• disorganized myocardium
  • the ventricular cardiomyocytes are disorganized, hypertrophic and display enlarged nuclei   (MGI Ref ID J:93176)
• increased heart weight
  • at 3 weeks of age, transgenic mice display a ~2-fold increase in heart weight to tibia length ratio   (MGI Ref ID J:109586)
• homeostasis/metabolism phenotype
• pulmonary edema
  • perivascular edema in the lungs is seen in transgenic mice that die suddenly   (MGI Ref ID J:93176)
• respiratory system phenotype
• pulmonary edema
  • perivascular edema in the lungs is seen in transgenic mice that die suddenly   (MGI Ref ID J:93176)

Tg(Myh6-Ppp3ca)37Eno/0

        Background Not Specified

• cardiovascular system phenotype
• cardiac hypertrophy
  • at 3 weeks of age, showed a 149% increase in heart weight/body weight ratio compared to wild-type   (MGI Ref ID J:94665)
• enlarged myocardial fiber
  • 34% increase in myocyte area compared to wild-type   (MGI Ref ID J:94665)
• muscle phenotype
• enlarged myocardial fiber
  • 34% increase in myocyte area compared to wild-type   (MGI Ref ID J:94665)

View Research Applications

Research Applications

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

Cardiovascular Research
Heart Abnormalities
      cardiomyopathy

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Tg(Myh6-Ppp3ca)37Eno
Allele Name		transgene insertion 37, Eric N Olson
Allele Type		Transgenic (random, expressed)
Common Name(s)		CN; CNA; CalTG; MHC-CnA;
Mutation Made By		Jeffery Molkentin,   Children's Hospital Medical Center
Strain of Origin		FVB
Expressed Gene		Ppp3ca, protein phosphatase 3, catalytic subunit, alpha isoform, mouse, laboratory
Promoter		Myh6, myosin, heavy polypeptide 6, cardiac muscle, alpha, murine, murine
Molecular Note		The promoter region of Myh6 drives expression of a constitutively active Ppp3ca cDNA in cardiomyocytes. This is a representative record representing Tg46, Tg22, Tg110, Tg106, Tg108, Tg41, Tg37, and Tg39 which vary in the number of copies of the transgene integrated but all have identical phenotypes. [MGI Ref ID J:93176]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(Myh6-Ppp3ca)37Eno STD PCR, Melt Curve Analysis
Tg(Myh6-Ppp3ca)37Eno STD PCR, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Molkentin JD; Lu JR; Antos CL; Markham B; Richardson J; Robbins J; Grant SR; Olson EN. 1998. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93(2):215-28. [PubMed: 9568714]  [MGI Ref ID J:93176]

Additional References

Tg(Myh6-Ppp3ca)37Eno related

Bierhuizen MF; Boulaksil M; van Stuijvenberg L; van der Nagel R; Jansen AT; Mutsaers NA; Yildirim C; van Veen TA; de Windt LJ; Vos MA; van Rijen HV. 2008. In calcineurin-induced cardiac hypertrophy expression of Nav1.5, Cx40 and Cx43 is reduced by different mechanisms. J Mol Cell Cardiol 45(3):373-84. [PubMed: 18662696]  [MGI Ref ID J:139953]

Bourajjaj M; Armand AS; da Costa Martins PA; Weijts B; van der Nagel R; Heeneman S; Wehrens XH; De Windt LJ. 2008. NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. J Biol Chem 283(32):22295-303. [PubMed: 18477567]  [MGI Ref ID J:139064]

Bousette N; Chugh S; Fong V; Isserlin R; Kim KH; Volchuk A; Backx PH; Liu P; Kislinger T; MacLennan DH; Emili A; Gramolini AO. 2010. Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by alpha-crystallin-B. Proc Natl Acad Sci U S A 107(43):18481-6. [PubMed: 20937869]  [MGI Ref ID J:165515]

Chang S; McKinsey TA; Zhang CL; Richardson JA; Hill JA; Olson EN. 2004. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24(19):8467-76. [PubMed: 15367668]  [MGI Ref ID J:93021]

Chu G; Carr AN; Young KB; Lester JW; Yatani A; Sanbe A; Colbert MC; Schwartz SM; Frank KF; Lampe PD; Robbins J; Molkentin JD; Kranias EG. 2002. Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure. Cardiovasc Res 54(1):105-16. [PubMed: 12062367]  [MGI Ref ID J:130415]

Dong D; Duan Y; Guo J; Roach DE; Swirp SL; Wang L; Lees-Miller JP; Sheldon RS; Molkentin JD; Duff HJ. 2003. Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels. Cardiovasc Res 57(2):320-32. [PubMed: 12566105]  [MGI Ref ID J:128687]

Espinoza-Derout J; Wagner M; Salciccioli L; Lazar JM; Bhaduri S; Mascareno E; Chaqour B; Siddiqui MA. 2009. Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1. Circ Res 104(12):1347-54. [PubMed: 19443839]  [MGI Ref ID J:164763]

Frey N; Barrientos T; Shelton JM; Frank D; Rutten H; Gehring D; Kuhn C; Lutz M; Rothermel B; Bassel-Duby R; Richardson JA; Katus HA; Hill JA; Olson EN. 2004. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med 10(12):1336-1343. [PubMed: 15543153]  [MGI Ref ID J:94665]

Gillis AM; Kavanagh KM; Mathison HJ; Somers JR; Zhan S; Duff HJ. 2004. Heart block in mice overexpressing calcineurin but not NF-AT3. Cardiovasc Res 64(3):488-95. [PubMed: 15537502]  [MGI Ref ID J:128869]

Guo J; Zhan S; Somers J; Westenbroek RE; Catterall WA; Roach DE; Sheldon RS; Lees-Miller JP; Li P; Shimoni Y; Duff HJ. 2006. Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin. Am J Physiol Heart Circ Physiol 291(6):H2669-79. [PubMed: 16751287]  [MGI Ref ID J:116463]

Guo L; Nakamura K; Lynch J; Opas M; Olson EN; Agellon LB; Michalak M. 2002. Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse. J Biol Chem 277(52):50776-9. [PubMed: 12377773]  [MGI Ref ID J:135415]

Heineke J; Auger-Messier M; Correll RN; Xu J; Benard MJ; Yuan W; Drexler H; Parise LV; Molkentin JD. 2010. CIB1 is a regulator of pathological cardiac hypertrophy. Nat Med 16(8):872-9. [PubMed: 20639889]  [MGI Ref ID J:163320]

Heineke J; Auger-Messier M; Xu J; Oka T; Sargent MA; York A; Klevitsky R; Vaikunth S; Duncan SA; Aronow BJ; Robbins J; Cromblehol TM; Molkentin JD. 2007. Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J Clin Invest 117(11):3198-210. [PubMed: 17975667]  [MGI Ref ID J:127378]

Ikeda S; He A; Kong SW; Lu J; Bejar R; Bodyak N; Lee KH; Ma Q; Kang PM; Golub TR; Pu WT. 2009. MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Mol Cell Biol 29(8):2193-204. [PubMed: 19188439]  [MGI Ref ID J:147774]

Oh M; Dey A; Gerard RD; Hill JA; Rothermel BA. 2010. The CCAAT/enhancer binding protein beta (C/EBPbeta) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4. J Biol Chem 285(22):16623-31. [PubMed: 20371871]  [MGI Ref ID J:163881]

Patrick DM; Montgomery RL; Qi X; Obad S; Kauppinen S; Hill JA; van Rooij E; Olson EN. 2010. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J Clin Invest 120(11):3912-6. [PubMed: 20978354]  [MGI Ref ID J:166911]

Petrashevskaya NN; Bodi I; Rubio M; Molkentin JD; Schwartz A. 2002. Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse. Cardiovasc Res 54(1):117-32. [PubMed: 12062368]  [MGI Ref ID J:130414]

Pinz I; Ostroy SE; Hoyer K; Osinska H; Robbins J; Molkentin JD; Ingwall JS. 2008. Calcineurin-induced energy wasting in a transgenic mouse model of heart failure. Am J Physiol Heart Circ Physiol 294(3):H1459-66. [PubMed: 18192216]  [MGI Ref ID J:132411]

Sanna B; Brandt EB; Kaiser RA; Pfluger P; Witt SA; Kimball TR; van Rooij E; De Windt LJ; Rothenberg ME; Tschop MH; Benoit SC; Molkentin JD. 2006. Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo. Proc Natl Acad Sci U S A 103(19):7327-32. [PubMed: 16648267]  [MGI Ref ID J:109586]

Sayen MR; Gustafsson AB; Sussman MA; Molkentin JD; Gottlieb RA. 2003. Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. Am J Physiol Cell Physiol 284(2):C562-70. [PubMed: 12397029]  [MGI Ref ID J:130997]

Sipione S; Ewen C; Shostak I; Michalak M; Bleackley RC. 2005. Impaired cytolytic activity in calreticulin-deficient CTLs. J Immunol 174(6):3212-9. [PubMed: 15749851]  [MGI Ref ID J:97687]

Somers JR; Beck PL; Lees-Miller JP; Roach D; Li Y; Guo J; Loken S; Zhan S; Semeniuk L; Duff HJ. 2008. iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin. Am J Physiol Heart Circ Physiol 295(3):H1122-H1131. [PubMed: 18621856]  [MGI Ref ID J:141285]

Sussman MA; Welch S; Walker A; Klevitsky R; Hewett TE; Witt SA; Kimball TR; Price R; Lim HW; Molkentin JD. 2000. Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice [see comments] Cardiovasc Res 46(1):90-101. [PubMed: 10727657]  [MGI Ref ID J:61245]

Wilkins BJ; De Windt LJ; Bueno OF; Braz JC; Glascock BJ; Kimball TF; Molkentin JD. 2002. Targeted Disruption of NFATc3, but Not NFATc4, Reveals an Intrinsic Defect in Calcineurin-Mediated Cardiac Hypertrophic Growth. Mol Cell Biol 22(21):7603-13. [PubMed: 12370307]  [MGI Ref ID J:79608]

Wu X; Chang B; Blair NS; Sargent M; York AJ; Robbins J; Shull GE; Molkentin JD. 2009. Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents. J Clin Invest 119(4):976-85. [PubMed: 19287093]  [MGI Ref ID J:149624]

Xu J; Gong NL; Bodi I; Aronow BJ; Backx PH; Molkentin JD. 2006. Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice. J Biol Chem 281(14):9152-62. [PubMed: 16469744]  [MGI Ref ID J:111573]

Xu J; Kimball TR; Lorenz JN; Brown DA; Bauskin AR; Klevitsky R; Hewett TE; Breit SN; Molkentin JD. 2006. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res 98(3):342-50. [PubMed: 16397142]  [MGI Ref ID J:118882]

Yatani A; Honda R; Tymitz KM; Lalli MJ; Molkentin JD. 2001. Enhanced Ca2+ channel currents in cardiac hypertrophy induced by activation of calcineurin-dependent pathway. J Mol Cell Cardiol 33(2):249-59. [PubMed: 11162130]  [MGI Ref ID J:127806]

Zhang CL; McKinsey TA; Chang S; Antos CL; Hill JA; Olson EN. 2002. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110(4):479-88. [PubMed: 12202037]  [MGI Ref ID J:78734]

Zhao G; Jeoung NH; Burgess SC; Rosaaen-Stowe KA; Inagaki T; Latif S; Shelton JM; McAnally J; Bassel-Duby R; Harris RA; Richardson JA; Kliewer SA. 2008. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 294(2):H936-43. [PubMed: 18083902]  [MGI Ref ID J:132373]

van Oort RJ; van Rooij E; Bourajjaj M; Schimmel J; Jansen MA; van der Nagel R; Doevendans PA; Schneider MD; van Echteld CJ; De Windt LJ. 2006. MEF2 activates a genetic program promoting chamber dilation and contractile dysfunction in calcineurin-induced heart failure. Circulation 114(4):298-308. [PubMed: 16847152]  [MGI Ref ID J:123084]

van Rooij E; Sutherland LB; Qi X; Richardson JA; Hill J; Olson EN. 2007. Control of stress-dependent cardiac growth and gene expression by a MicroRNA. Science 316(5824):575-9. [PubMed: 17379774]  [MGI Ref ID J:120908]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB29

Colony Maintenance

Breeding & Husbandry	When maintained as a live colony, hemizygotes may be bred.
Mating System	Hemizygote x Noncarrier         (Female x Male)   02-APR-11

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

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	Noncarrier
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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