Lost in transgenesis: A User's guide for genetically manipulating the mouse in cardiac research

Circulation Research

Volumn 111, Issue 6, 2012, Pages 761-777

  Davis, Jennifer ^a,b   Maillet, Marjorie ^a   Miano, Joseph M ^c   Molkentin, Jeffery D ^a,b  

^a UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

^b CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

^c UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY   (United States)

Author keywords

genetics; mouse heart development; transgene; transgenic mice

Indexed keywords

COMPLEMENTARY DNA; GREEN FLUORESCENT PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE 7; MYOSIN HEAVY CHAIN ALPHA;

ARTIFICIAL CHROMOSOME; DNA MODIFICATION; GENE INSERTION; GENE TARGETING; GENETIC DRIFT; GENOTYPE; LOSS OF FUNCTION MUTATION; NONHUMAN; PHENOTYPE; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SEX CHROMOSOME; TRANSGENIC ANIMAL; TRANSGENICS;

ANIMALS; BIOMEDICAL RESEARCH; DISEASE MODELS, ANIMAL; GUIDELINES AS TOPIC; HEART; HUMANS; MICE; MICE, KNOCKOUT; MICE, TRANSGENIC; MYOCARDIUM;

EID: 84865838098     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.111.262717     Document Type: Review

References (128)

1. Costantini F, Lacy E. Introduction of a rabbit beta-globin gene into the mouse germ line. Nature. 1981;294:92-94.
2. Gordon JW, Ruddle FH. Integration and stable germ line transmission of genes injected into mouse pronuclei. Science. 1981;214:1244-1246.
3. Harbers K, Jahner D, Jaenisch R. Microinjection of cloned retroviral genomes into mouse zygotes: integration and expression in the animal. Nature. 1981;293:540-542.
4. Palmiter RD, Brinster RL. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465-499.
5. Subramaniam A, Jones WK, Gulick J, Wert S, Neumann J, Robbins J. Tissue-specific regulation of the alpha-myosin heavy chain gene promoter in transgenic mice. J Biol Chem. 1991;266:24613-24620.
6. Skarnes WC, Rosen B, West AP, et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474: 337-342.
7. Stanford WL, Cohn JB, Cordes SP. Gene-trap mutagenesis: past, present and beyond. Nat Rev Genet. 2001;2:756-768.
8. Stanford WL, Epp T, Reid T, Rossant J. Gene trapping in embryonic stem cells. Methods Enzymol. 2006;420:136-162.
9. De Windt LJ, Lim HW, Bueno OF, Liang Q, Delling U, Braz JC, Glascock BJ, Kimball TF, del Monte F, Hajjar RJ, Molkentin JD. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci USA. 2001;98:3322-3327.
10. Hill JA, Rothermel B, Yoo KD, Cabuay B, Demetroulis E, Weiss RM, Kutschke W, Bassel-Duby R, Williams RS. Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J Biol Chem. 2002;277:10251-10255.
11. Rothermel BA, McKinsey TA, Vega RB, Nicol RL, Mammen P, Yang J, Antos CL, Shelton JM, Bassel-Duby R, Olson EN, Williams RS. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci USA. 2001;98: 3328-3333.
12. Zou Y, Hiroi Y, Uozumi H, Takimoto E, Toko H, Zhu W, Kudoh S, Mizukami M, Shimoyama M, Shibasaki F, Nagai R, Yazaki Y, Komuro I. Calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy. Circulation. 2001;104:97-101.
13. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, Molkentin JD. Impaired cardiac hypertrophic response in Calcineurin Abeta-deficient mice. Proc Natl Acad Sci USA. 2002;99: 4586-4591.
14. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998;93:215-228.
15. Soriano P. Gene targeting in ES cells. Annu Rev Neurosci. 1995; 18:1-18.
16. Geisterfer-Lowrance AA, Christe M, Conner DA, Ingwall JS, Schoen FJ, Seidman CE, Seidman JG. A mouse model of familial hypertrophic cardiomyopathy. Science. 1996;272:731-734.
17. Fatkin D, McConnell BK, Mudd JO, Semsarian C, Moskowitz IG, Schoen FJ, Giewat M, Seidman CE, Seidman JG. An abnormal Ca(2) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. J Clin Invest. 2000;106:1351-1359.
18. Schmitt JP, Semsarian C, Arad M, Gannon J, Ahmad F, Duffy C, Lee RT, Seidman CE, Seidman JG. Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy. Circulation. 2003;108:1133-1138.
19. Semsarian C, Maron BJ. Sudden cardiac death in the young. Med J Aust. 2002;176:148-149.
20. Vikstrom KL, Factor SM, Leinwand LA. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy. Mol Med. 1996;2:556-567.
21. Georgakopoulos D, Christe ME, Giewat M, Seidman CM, Seidman JG, Kass DA. The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an alpha-cardiac myosin heavy chain missense mutation. Nat Med. 1999;5:327-330.
22. Sun Y, Liang X, Najafi N, Cass M, Lin L, Cai CL, Chen J, Evans SM. Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev Biol. 2007;304:286-296.
23. Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, Ang SL, Meloche S. An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep. 2003;4:964-968.
24. Kehat I, Davis J, Tiburcy M, Accornero F, Saba-El-Leil MK, Maillet M, York AJ, Lorenz JN, Zimmermann WH, Meloche S, Molkentin JD. Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth. Circ Res. 2011;108: 176-183.
25. Braun T, Bober E, Rudnicki MA, Jaenisch R, Arnold HH. MyoD expression marks the onset of skeletal myogenesis in Myf-5 mutant mice. Development. 1994;120:3083-3092.
26. Patapoutian A, Yoon JK, Miner JH, Wang S, Stark K, Wold B. Disruption of the mouse MRF4 gene identifies multiple waves of myogenesis in the myotome. Development. 1995;121:3347-3358.
27. Zhang W, Behringer RR, Olson EN. Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies. Genes Dev. 1995;9:1388-1399.
28. Lynch J.M. MM, Vanhoutte D, Schloemer A, Blair S, Lynch KA, Okada T, Aronow B, Osinska H, Prywes R, Lorenz J, Mori K, Lawler J, Robbins J, Molkentin J.D. A thrombospondin-dependent pathway for a protective ER stress response. Cell. 2012;149:1-12.
29. Morkin E. Regulation of myosin heavy chain genes in the heart. Circulation. 1993;87:1451-1460.
30. Ng WA, Grupp IL, Subramaniam A, Robbins J. Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart. Circ Res. 1991;68:1742-1750.
31. Jones WK, Sanchez A, Robbins J. Murine pulmonary myocardium: developmental analysis of cardiac gene expression. Dev Dyn. 1994;200: 117-128.
32. Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest. 1997;100: 2315-2324.
33. Miyata S, Minobe W, Bristow MR, Leinwand LA. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res. 2000;86:386-390.
34. Colbert MC, Hall DG, Kimball TR, Witt SA, Lorenz JN, Kirby ML, Hewett TE, Klevitsky R, Robbins J. Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice. J Clin Invest. 1997;100:1958-1968.
35. Rindt H, Gulick J, Knotts S, Neumann J, Robbins J. In vivo analysis of the murine beta-myosin heavy chain gene promoter. J Biol Chem. 1993;268:5332-5338.
36. Franz WM, Brem G, Katus HA, Klingel K, Hofschneider PH, Kandolf R. Characterization of a cardiac-selective and developmentally upregulated promoter in transgenic mice. Cardioscience. 1994;5: 235-243.
37. Hunter JJ, Tanaka N, Rockman HA, Ross J Jr, Chien KR. Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J Biol Chem. 1995;270:23173-23178.
38. Lee KJ, Hickey R, Zhu H, Chien KR. Positive regulatory elements (HF-1a and HF-1b) and a novel negative regulatory element (HF-3) mediate ventricular muscle-specific expression of myosin light-chain 2-luciferase fusion genes in transgenic mice. Mol Cell Biol. 1994;14: 1220-1229.
39. O'Brien TX, Lee KJ, Chien KR. Positional specification of ventricular myosin light chain 2 expression in the primitive murine heart tube. Proc Natl Acad Sci USA. 1993;90:5157-5161.
40. Wang Q, Reiter RS, Huang QQ, Jin JP, Lin JJ. Comparative studies on the expression patterns of three troponin T genes during mouse development. Anat Rec. 2001;263:72-84.
41. Wang Q, Sigmund CD, Lin JJ. Identification of cis elements in the cardiac troponin T gene conferring specific expression in cardiac muscle of transgenic mice. Circ Res. 2000;86:478-484.
42. Hahn HS, Yussman MG, Toyokawa T, Marreez Y, Barrett TJ, Hilty KC, Osinska H, Robbins J, Dorn GW II. Ischemic protection and myofibrillar cardiomyopathy: dose-dependent effects of in vivo deltaPKC inhibition. Circ Res. 2002;91:741-748.
43. Mayr M, Metzler B, Chung YL, McGregor E, Mayr U, Troy H, Hu Y, Leitges M, Pachinger O, Griffiths JR, Dunn MJ, Xu Q. Ischemic preconditioning exaggerates cardiac damage in PKC-delta null mice. Am J Physiol Heart Circ Physiol. 2004;287:H946-H956.
44. Leitges M, Mayr M, Braun U, Mayr U, Li C, Pfister G, Ghaffari-Tabrizi N, Baier G, Hu Y, Xu Q. Exacerbated vein graft arteriosclerosis in protein kinase Cdelta-null mice. J Clin Invest. 2001;108:1505-1512.
45. Mayr M, Chung YL, Mayr U, McGregor E, Troy H, Baier G, Leitges M, Dunn MJ, Griffiths JR, Xu Q. Loss of PKC-delta alters cardiac metabolism. Am J Physiol Heart Circ Physiol. 2004;287:H937-H945.
46. James J, Robbins J. Molecular remodeling of cardiac contractile function. Am J Physiol. 1997;273:H2105-H2118.
47. Palermo J, Gulick J, Colbert M, Fewell J, Robbins J. Transgenic remodeling of the contractile apparatus in the mammalian heart. Circ Res. 1996;78:504-509.
48. Heaney JD, Bronson SK. Artificial chromosome-based transgenes in the study of genome function. Mamm Genome. 2006;17:791-807.
49. Long X, Miano JM. Remote control of gene expression. J Biol Chem. 2007;282:15941-15945.
50. Gossen M, Bonin AL, Freundlieb S, Bujard H. Inducible gene expression systems for higher eukaryotic cells. Curr Opin Biotechnol. 1994;5:516-520.
51. Mansuy IM, Winder DG, Moallem TM, Osman M, Mayford M, Hawkins RD, Kandel ER. Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron. 1998;21:257-265.
52. Sanbe A, Gulick J, Hanks MC, Liang Q, Osinska H, Robbins J. Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res. 2003;92:609-616.
53. McCloskey DT, Turnbull L, Swigart PM, Zambon AC, Turcato S, Joho S, Grossman W, Conklin BR, Simpson PC, Baker AJ. Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression. Physiol Genom. 2005;22:118-126.
54. Berry JM, Le V, Rotter D, Battiprolu PK, Grinsfelder B, Tannous P, Burchfield JS, Czubryt M, Backs J, Olson EN, Rothermel BA, Hill JA. Reversibility of adverse, calcineurin-dependent cardiac remodeling. Circ Res. 2011;109:407-417.
55. Petrich BG, Molkentin JD, Wang Y. Temporal activation of c-Jun N-terminal kinase in adult transgenic heart via cre-loxP-mediated DNA recombination. FASEB J. 2003;17:749-751.
56. Sohal DS, Nghiem M, Crackower MA, Witt SA, Kimball TR, Tymitz KM, Penninger JM, Molkentin JD. Temporally regulated and tissuespecific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ Res. 2001;89:20-25.
57. Chakraborty S, Yutzey KE. Tbx20 regulation of cardiac cell proliferation and lineage specialization during embryonic and fetal development in vivo. Dev Biol. 2012;363:234-246.
58. Liang Q, Bueno OF, Wilkins BJ, Kuan CY, Xia Y, Molkentin JD. c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signaling. EMBO J. 2003;22:5079-5089.
59. Nakanishi T, Kuroiwa A, Yamada S, Isotani A, Yamashita A, Tairaka A, Hayashi T, Takagi T, Ikawa M, Matsuda Y, Okabe M. FISH analysis of 142 EGFP transgene integration sites into the mouse genome. Genomics. 2002;80:564-574.
60. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 2000;19:6341-6350.
61. Liang Z, Breman AM, Grimes BR, Rosen ED. Identifying and genotyping transgene integration loci. Transgenic Res. 2008;17:979-983.
62. Ochman H, Gerber AS, Hartl DL. Genetic applications of an inverse polymerase chain reaction. Genetics. 1988;120:621-623.
63. Matzke AJ, Matzke MA. Position effects and epigenetic silencing of plant transgenes. Curr Opin Plant Biol. 1998;1:142-148.
64. Scrable H, Stambrook PJ. Activation of the Lac repressor in the transgenic mouse. Genetics. 1997;147:297-304.
65. D'Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW II. Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA. 1997;94:8121-8126.
66. Syed F, Odley A, Hahn HS, Brunskill EW, Lynch RA, Marreez Y, Sanbe A, Robbins J, Dorn GW II. Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circ Res. 2004;95: 1200-1206.
67. James J, Osinska H, Hewett TE, Kimball T, Klevitsky R, Witt S, Hall DG, Gulick J, Robbins J. Transgenic over-expression of a motor protein at high levels results in severe cardiac pathology. Transgenic Res. 1999;8:9-22.
68. Chu G, Kranias EG. Phospholamban as a therapeutic modality in heart failure. Novartis Found Symp. 2006;274:156-171.
69. Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res. 1994;75:401-409.
70. Slack JP, Grupp IL, Luo W, Kranias EG. Phospholamban ablation enhances relaxation in the murine soleus. Am J Physiol. 1997;273: C1-C6.
71. Lin Q, Schwarz J, Bucana C, Olson EN. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science. 1997;276:1404-1407.
72. Lin Q, Lu J, Yanagisawa H, Webb R, Lyons GE, Richardson JA, Olson EN. Requirement of the MADS-box transcription factor MEF2C for vascular development. Development. 1998;125:4565-4574.
73. Moses KA, DeMayo F, Braun RM, Reecy JL, Schwartz RJ. Embryonic expression of an Nkx2-5/Cre gene using ROSA26 reporter mice. Genesis. 2001;31:176-180.
74. Jay PY, Harris BS, Maguire CT, Buerger A, Wakimoto H, Tanaka M, Kupershmidt S, Roden DM, Schultheiss TM, O'Brien TX, Gourdie RG, Berul CI, Izumo S. Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. J Clin Invest. 2004;113:1130-1137.
75. Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Elliott DA, Barnett L, Koentgen F, Robb L, Feneley M, Harvey RP. Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res. 2000;87:888-895.
76. Oka T, Maillet M, Watt AJ, Schwartz RJ, Aronow BJ, Duncan SA, Molkentin JD. Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res. 2006; 98:837-845.
77. Agah R, Frenkel PA, French BA, Michael LH, Overbeek PA, Schneider MD. Gene recombination in postmitotic cells: targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J Clin Invest. 1997;100:169-179.
78. Schmidt EE, Taylor DS, Prigge JR, Barnett S, Capecchi MR. Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids. Proc Natl Acad Sci USA. 2000;97:13702-13707.
79. Verrou C, Zhang Y, Zurn C, Schamel WW, Reth M. Comparison of the tamoxifen regulated chimeric Cre recombinases MerCreMer and CreMer. Biol Chem. 1999;380:1435-1438.
80. Feil R, Wagner J, Metzger D, Chambon P. Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun. 1997;237:752-757.
81. Andersson KB, Winer LH, Mork HK, Molkentin JD, Jaisser F. Tamoxifen administration routes and dosage for inducible Cre-mediated gene disruption in mouse hearts. Transgenic Res. 2010;19:715-725.
82. Hall ME, Smith G, Hall JE, Stec DE. Systolic dysfunction in cardiacspecific ligand-inducible MerCreMer transgenic mice. Am J Physiol Heart Circ Physiol. 2011;301:H253-H260.
83. Koitabashi N, Bedja D, Zaiman AL, Pinto YM, Zhang M, Gabrielson KL, Takimoto E, Kass DA. Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models. Circ Res. 2009;105:12-15.
84. Kiermayer C, Conrad M, Schneider M, Schmidt J, Brielmeier M. Optimization of spatiotemporal gene inactivation in mouse heart by oral application of tamoxifen citrate. Genesis. 2007;45:11-16.
85. Minamino T, Gaussin V, DeMayo FJ, Schneider MD. Inducible gene targeting in postnatal myocardium by cardiac-specific expression of a hormone-activated Cre fusion protein. Circ Res. 2001;88:587-592.
86. Xiong D, Heyman NS, Airey J, Zhang M, Singer CA, Rawat S, Ye L, Evans R, Burkin DJ, Tian H, McCloskey DT, Valencik M, Britton FC, Duan D, Hume JR. Cardiac-specific, inducible ClC-3 gene deletion eliminates native volume-sensitive chloride channels and produces myocardial hypertrophy in adult mice. J Mol Cell Cardiol. 2010;48:211-219.
87. Wu B, Zhou B, Wang Y, Cheng HL, Hang CT, Pu WT, Chang CP. Inducible cardiomyocyte-specific gene disruption directed by the rat Tnnt2 promoter in the mouse. Genesis. 2010;48:63-72.
88. Novak A, Guo C, Yang W, Nagy A, Lobe CG. Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis. 2000;28:147-155.
89. Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007;13:970-974.
90. Taketo M, Schroeder AC, Mobraaten LE, Gunning KB, Hanten G, Fox RR, Roderick TH, Stewart CL, Lilly F, Hansen CT. FVB/N: an inbred mouse strain preferable for transgenic analyses. Proc Natl Acad Sci USA. 1991;88:2065-2069.
91. Seong E, Saunders TL, Stewart CL, Burmeister M. To knockout in 129 or in C57BL/6: that is the question. Trends Genet. 2004;20:59-62.
92. Ware CB, Siverts LA, Nelson AM, Morton JF, Ladiges WC. Utility of a C57BL/6 ES line versus 129 ES lines for targeted mutations in mice. Transgenic Res. 2003;12:743-746.
93. Barnabei MS, Palpant NJ, Metzger JM. Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains. Physiol Genomics. 2010;42A:103-113.
94. Bendall JK, Heymes C, Wright TJ, Wheatcroft S, Grieve DJ, Shah AM, Cave AC. Strain-dependent variation in vascular responses to nitric oxide in the isolated murine heart. J Mol Cell Cardiol. 2002;34: 1325-1333.
95. Blizard DA, Welty R. Cardiac activity in the mouse: strain differences. J Comp Physiol Psychol. 1971;77:337-344.
96. Shah AP, Siedlecka U, Gandhi A, Navaratnarajah M, Al-Saud SA, Yacoub MH, Terracciano CM. Genetic background affects function and intracellular calcium regulation of mouse hearts. Cardiovasc Res. 2010; 87:683-693.
97. Michele DE, Gomez CA, Hong KE, Westfall MV, Metzger JM. Cardiac dysfunction in hypertrophic cardiomyopathy mutant tropomyosin mice is transgene-dependent, hypertrophy-independent, and improved by beta-blockade. Circ Res. 2002;91:255-262.
98. Prabhakar R, Boivin GP, Grupp IL, Hoit B, Arteaga G, Solaro JR, Wieczorek DF. A familial hypertrophic cardiomyopathy alphatropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol. 2001;33:1815-1828.
99. Barrick CJ, Rojas M, Schoonhoven R, Smyth SS, Threadgill DW. Cardiac response to pressure overload in 129S1/SvImJ and C57BL/6J mice: temporal-and background-dependent development of concentric left ventricular hypertrophy. Am J Physiol Heart Circ Physiol. 2007; 292:H2119-H2130.
100. Liu Q, Chen X, Macdonnell SM, Kranias EG, Lorenz JN, Leitges M, Houser SR, Molkentin JD. Protein kinase C, but not PKCor PKC, regulates contractility and heart failure susceptibility: implications for ruboxistaurin as a novel therapeutic approach. Circ Res. 2009;105: 194-200.
101. Kass DA, Hare JM, Georgakopoulos D. Murine cardiac function: a cautionary tail. Circ Res. 1998;82:519-522.
102. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415: 198-205.
103. Lompre AM, Nadal-Ginard B, Mahdavi V. Expression of the cardiac ventricular alpha-and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem. 1984;259:6437-6446.
104. Nadal-Ginard B, Mahdavi V. Molecular basis of cardiac performance: plasticity of the myocardium generated through protein isoform switches. J Clin Invest. 1989;84:1693-1700.
105. Harris DE, Work SS, Wright RK, Alpert NR, Warshaw DM. Smooth, cardiac and skeletal muscle myosin force and motion generation assessed by cross-bridge mechanical interactions in vitro. J Muscle Res Cell Motil. 1994;15:11-19.
106. Herron TJ, McDonald KS. Small amounts of alpha-myosin heavy chain isoform expression significantly increase power output of rat cardiac myocyte fragments. Circ Res. 2002;90:1150-1152.
107. Buttrick PM, Kaplan ML, Kitsis RN, Leinwand LA. Distinct behavior of cardiac myosin heavy chain gene constructs in vivo: discordance with in vitro results. Circ Res. 1993;72:1211-1217.
108. Sanbe A, James J, Tuzcu V, Nas S, Martin L, Gulick J, Osinska H, Sakthivel S, Klevitsky R, Ginsburg KS, Bers DM, Zinman B, Lakatta EG, Robbins J. Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy. Circulation. 2005;111:2330-2338.
109. Parsons SA, Millay DP, Wilkins BJ, Bueno OF, Tsika GL, Neilson JR, Liberatore CM, Yutzey KE, Crabtree GR, Tsika RW, Molkentin JD. Genetic loss of calcineurin blocks mechanical overload-induced skeletal muscle fiber type switching but not hypertrophy. J Biol Chem. 2004; 279:26192-26200.
110. Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, Hogan BL. An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev. 2003;17:2362-2367.
111. Maillet M, Davis J, Auger-Messier M, York A, Osinska H, Piquereau J, Lorenz JN, Robbins J, Ventura-Clapier R, Molkentin JD. Heart-specific deletion of CnB1 reveals multiple mechanisms whereby calcineurin regulates cardiac growth and function. J Biol Chem. 2010;285: 6716-6724.
112. Reecy JM, Li X, Yamada M, DeMayo FJ, Newman CS, Harvey RP, Schwartz RJ. Identification of upstream regulatory regions in the heartexpressed homeobox gene Nkx2-5. Development. 1999;126:839-849.
113. Lien CL, Wu C, Mercer B, Webb R, Richardson JA, Olson EN. Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. Development. 1999;126:75-84.
114. Kwon C, Arnold J, Hsiao EC, Taketo MM, Conklin BR, Srivastava D. Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proc Natl Acad Sci USA. 2007;104:10894-10899.
115. McFadden DG, Barbosa AC, Richardson JA, Schneider MD, Srivastava D, Olson EN. The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosagedependent manner. Development. 2005;132:189-201.
116. Dodou E, Verzi MP, Anderson JP, Xu SM, Black BL. Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development. 2004;131: 3931-3942.
117. Verzi MP, McCulley DJ, De Val S, Dodou E, Black BL. The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev Biol. 2005;287:134-145.
118. Chen J, Kubalak SW, Chien KR. Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development. 1998;125:1943-1949.
119. Kang J, Nathan E, Xu SM, Tzahor E, Black BL. Isl1 is a direct transcriptional target of Forkhead transcription factors in second-heartfield- derived mesoderm. Dev Biol. 2009;334:513-522.
120. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003;5:877-889.
121. Srinivas S, Watanabe T, Lin CS, William CM, Tanabe Y, Jessell TM, Costantini F. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol. 2001;1:4.
122. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR. Postnatal isl1 cardioblasts enter fully differentiated cardiomyocyte lineages. Nature. 2005;433:647-653.
123. Li L, Miano JM, Cserjesi P, Olson EN. SM22 alpha, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis. Circ Res. 1996;78:188-195.
124. Li L, Miano JM, Mercer B, Olson EN. Expression of the SM22alpha promoter in transgenic mice provides evidence for distinct transcriptional regulatory programs in vascular and visceral smooth muscle cells. J Cell Biol. 1996;132:849-859.
125. Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B, Hammer RE, Herz J, Kuhn M. Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci USA. 2002;99:7142-7147.
126. Miano JM, Ramanan N, Georger MA, de Mesy Bentley KL, Emerson RL, Balza RO Jr, Xiao Q, Weiler H, Ginty DD, Misra RP. Restricted inactivation of serum response factor to the cardiovascular system. Proc Natl Acad Sci USA. 2004;101:17132-17137.
127. Minamisawa S, Hoshijima M, Chu G, Ward CA, Frank K, Gu Y, Martone ME, Wang Y, Ross J Jr, Kranias EG, Giles WR, Chien KR. Chronic phospholamban- sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell. 1999;99:313-322.
128. Heineke J, Auger-Messier M, Correll RN, Xu J, Benard MJ, Yuan W, Drexler H, Parise LV, Molkentin JD. CIB1 is a regulator of pathological cardiac hypertrophy. Nat Med. 2010;16:872-879.