Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits
Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50% of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans.
Vyšlo v časopise:
Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits. PLoS Genet 8(5): e32767. doi:10.1371/journal.pgen.1002690
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002690
Souhrn
Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50% of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans.
Zdroje
1. HoffmanJIKaplanS 2002 The incidence of congenital heart disease. J Am Coll Cardiol 39 1890 1900
2. BottoLDCorreaAEricksonJD 2001 Racial and temporal variations in the prevalence of heart defects. Pediatrics 107 E32
3. PierpontMEBassonCTBensonDWJrGelbBDGigliaTM 2007 Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115 3015 3038
4. JenkinsKJCorreaAFeinsteinJABottoLBrittAE 2007 Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115 2995 3014
5. SrivastavaD 2006 Making or breaking the heart: from lineage determination to morphogenesis. Cell 126 1037 1048
6. GargV 2006 Insights into the genetic basis of congenital heart disease. Cell Mol Life Sci 63 1141 1148
7. BassonCTBachinskyDRLinRCLeviTElkinsJA 1997 Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15 30 35
8. BruneauBGNemerGSchmittJPCharronFRobitailleL 2001 A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106 709 721
9. SchottJJBensonDWBassonCTPeaseWSilberbachGM 1998 Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281 108 111
10. LyonsIParsonsLMHartleyLLiRAndrewsJE 1995 Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9 1654 1666
11. BibenCWeberRKestevenSStanleyEMcDonaldL 2000 Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circulation research 87 888 895
12. GargVKathiriyaISBarnesRSchlutermanMKKingIN 2003 GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424 443 447
13. RajagopalSKMaQOblerDShenJManichaikulA 2007 Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol 43 677 685
14. Tomita-MitchellAMaslenCLMorrisCDGargVGoldmuntzE 2007 GATA4 sequence variants in patients with congenital heart disease. J Med Genet 44 779 783
15. ZhangWLiXShenAJiaoWGuanX 2008 GATA4 mutations in 486 Chinese patients with congenital heart disease. Eur J Med Genet 51 527 535
16. ButlerTLEspositoGBlueGMColeADCostaMW 2010 GATA4 mutations in 357 unrelated patients with congenital heart malformation. Genet Test Mol Biomarkers 14 797 802
17. MolkentinJDLinQDuncanSAOlsonEN 1997 Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 11 1061 1072
18. KuoCTMorriseyEEAnandappaRSigristKLuMM 1997 GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11 1048 1060
19. HiroiYKudohSMonzenKIkedaYYazakiY 2001 Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet 28 276 280
20. MoskowitzIPKimJBMooreMLWolfCMPetersonMA 2007 A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell 129 1365 1376
21. MaitraMSchlutermanMKNicholsHARichardsonJALoCW 2009 Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol 326 368 377
22. SarkozyAContiENeriCD'AgostinoRDigilioMC 2005 Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factors. J Med Genet 42 e16
23. PuWTIshiwataTJuraszekALMaQIzumoS 2004 GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol 275 235 244
24. WattAJBattleMALiJDuncanSA 2004 GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci U S A 101 12573 12578
25. ZeisbergEMMaQJuraszekALMosesKSchwartzRJ 2005 Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest 115 1522 1531
26. Rivera-FelicianoJLeeKHKongSWRajagopalSMaQ 2006 Development of heart valves requires Gata4 expression in endothelial-derived cells. Development 133 3607 3618
27. CrispinoJDLodishMBThurbergBLLitovskySHCollinsT 2001 Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev 15 839 844
28. ChangYFImamJSWilkinsonMF 2007 The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76 51 74
29. MolkentinJD 2000 The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 275 38949 38952
30. BrownCO3rdChiXGarcia-GrasEShiraiMFengXHSchwartzRJ 2004 The cardiac determination factor, Nkx2-5, is activated by mutual co-factors GATA-4 and Smad1/4 via a novel upstream enhancer. J Biol Chem 279 10659 10669
31. DodouEVerziMPAndersonJPXuSMBlackBL 2004 Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development 131 3931 3942
32. RojasASchachterleWXuSMMartinFBlackBL 2010 Direct transcriptional regulation of Gata4 during early endoderm specification is controlled by FoxA2 binding to an intronic enhancer. Dev Biol 346 346 355
33. HoltzingerARosenfeldGEEvansT 2010 Gata4 directs development of cardiac-inducing endoderm from ES cells. Dev Biol 337 63 73
34. DuncanSANagyAChanW 1997 Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(−/−) embryos. Development 124 279 287
35. ArtusJPiliszekAHadjantonakisAK 2011 The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. Dev Biol 350 393 404
36. SoudaisCBielinskaMHeikinheimoMMacArthurCANaritaN 1995 Targeted mutagenesis of the transcription factor GATA-4 gene in mouse embryonic stem cells disrupts visceral endoderm differentiation in vitro. Development 121 3877 3888
37. RojasAKongSWAgarwalPGillissBPuWT 2008 GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium. Mol Cell Biol 28 5420 5431
38. WalshSPontenAFleischmannBKJovingeS 2010 Cardiomyocyte cell cycle control and growth estimation in vivo–an analysis based on cardiomyocyte nuclei. Cardiovasc Res 86 365 373
39. KisanukiYYHammerREMiyazakiJWilliamsSCRichardsonJA 2001 Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol 230 230 242
40. GaussinVVan de PutteTMishinaYHanksMCZwijsenA 2002 Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci U S A 99 2878 2883
41. McFaddenDGBarbosaACRichardsonJASchneiderMDSrivastavaD 2005 The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development 132 189 201
42. NadeauMGeorgesROLaforestBYamakALefebvreC 2010 An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. Proc Natl Acad Sci U S A 107 19356 19361
43. LaForestBAndelfingerGNemerM 2011 Loss of Gata5 in mice leads to bicuspid aortic valve. J Clin Invest 131 2876 2887
44. LaForestBNemerM 2011 GATA5 interacts with GATA4 and GATA6 in outflow tract development. Dev Biol 358 368 378
45. PehlivanTPoberBRBruecknerMGarrettSSlaughR 1999 GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am J Med Genet 83 201 206
46. SherrCJRobertsJM 2004 Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18 2699 2711
47. KozarKCiemerychMARebelVIShigematsuHZagozdzonA 2004 Mouse development and cell proliferation in the absence of D-cyclins. Cell 118 477 491
48. GargVYamagishiCHuTKathiriyaISYamagishiH 2001 Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev Biol 235 62 73
49. SchlutermanMKKrysiakAEKathiriyaISAbateNChandaliaM 2007 Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease. Am J Med Genet Part A 143A 817 823
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 5
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Inactivation of a Novel FGF23 Regulator, FAM20C, Leads to Hypophosphatemic Rickets in Mice
- Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat
- Slowing Replication in Preparation for Reduction
- Deletion of PTH Rescues Skeletal Abnormalities and High Osteopontin Levels in Mice