Abstract
In recent years, impressive advances have occurred in our understanding of transcriptional regulation of cardiac development. These insights have begun to elucidate the mystery of congenital heart disease at the molecular level. In addition, the molecular pathways emerging from the study of cardiac development are being applied to the understanding of adult cardiac disease. Preliminary results support the contention that a thorough understanding of molecular programs governing cardiac morphogenesis will provide important insights into the pathogenesis of human cardiac diseases. This review will focus on examples of transcription factors that play critical roles at various phases of cardiac development and their relevance to cardiac disease. This is an exciting and burgeoning area of investigation. It is not possible to be all-inclusive, and the reader will note important efforts in the areas of cardiomyocyte determination, left-right asymmetry, cardiac muscular dystrophies, electrophysiology and vascular disease are not covered. For a more complete discussion, the reader is referred to recent reviews including the excellent compilation of observations assembled by Harvey and Rosenthal (1).
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- DGS:
-
DiGeorge syndrome
- SRF:
-
serum response factor
- TGF:
-
transforming growth factor
- ECM:
-
extracellular matrix
References
Harvey RP, Rosenthal N 1999 Heart Development. Academic Press, San Diego, pp 1–488.
Fishman MC, Chien KR 1997 Fashioning the vertebrate heart: earliest embryonic decisions. Development 124: 2099–2117.
Olson EN, Srivastava D 1996 Molecular pathways controlling heart development. Science 272: 671–676.
Kirby ML, Gale TF, Stewart DE 1983 Neural crest cells contribute to normal aorticopulmonary septation. Science 220: 1059–1061.
Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM 1997 GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Gene Dev 11: 1048–1060.
Molkentin JD, Lin Q, Duncan SA, Olson EN 1997 Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Gene Dev 11: 1061–1072.
Orkin SH 1992 GATA-binding transcription factors in hematopoietic cells. Blood 80: 575–581.
Weiss MJ, Orkin SH 1995 GATA transcription factors: key regulators of hematopoiesis. Exp Hematol 23: 99–107.
Laverriere AC, MacNeill C, Mueller C, Poelmann RE, Burch JB, Evans T 1994 GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. J Biol Chem 269: 23177–23184.
Charron F, Nemer M 1999 GATA transcription factors and cardiac development. Semin Cell Dev Biol 10: 85–91.
Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M 1997 The cardiac transcription factors Nkx2–5 and GATA-4 are mutual cofactors. Embo J 16: 5687–5696.
Sepulveda JL, Belaguli N, Nigam V, Chen CY, Nemer M, Schwartz RJ 1998 GATA-4 and Nkx-2. Mol Cell Biol 18: 3405–3415.
Narita N, Bielinska M, Wilson DB 1997 Wild-type endoderm abrogates the ventral developmental defects associated with GATA-4 deficiency in the mouse. Dev Biol 189: 270–274.
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: 215–228.
Olson EN, Molkentin JD 1999 Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype?. Circ Res 84: 623
Sussman MA, Lim HW, Gude N, Taigen T, Olson EN, Robbins J, Colbert MC, Gualberto A, Wieczorek DF, Molkentin JD 1998 Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 281: 1690–1693.
Tsao L, Neville C, Musaro A, McCullagh KJ, Rosenthal N 2000 Revisiting calcineurin and human heart failure. Nat Med 6: 2–3.
Lim HW, Molkentin JD 1999 Calcineurin and human heart failure. Nat Med 5: 246–247.
Ding B, Price RL, Borg TK, Weinberg EO, Halloran PF, Lorell BH 1999 Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin. Circ Res 84: 729–734.
Zhang W, Kowal RC, Rusnak F, Sikkink RA, Olson EN, Victor RG 1999 Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats. Circ Res 84: 722–728.
Lim HW, Molkentin JD 2000 Reply to revisiting calcineurin and human heart failure. Nat Med 6: 3
Krumlauf R, Marshall H, Studer M, Nonchev S, Sham MH, Lumsden A 1993 Hox homeobox genes and regionalisation of the nervous system. J Neurobiol 24: 1328–1340.
Bao ZZ, Bruneau BG, Seidman JG, Seidman CE, Cepko CL 1999 Regulation of chamber-specific gene expression in the developing heart by Irx4. Science 283: 1161–1164.
Srivastava D, Cserjesi P, Olson EN 1995 A subclass of bHLH proteins required for cardiac morphogenesis. Science 270: 1995–1999.
Srivastava D, Thomas T, Lin Q, Kirby ML, Brown D, Olson EN 1997 Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat Genet 16: 154–160.
Thomas T, Yamagishi H, Overbeek PA, Olson EN, Srivastava D 1998 The bHLH factors, dHAND and eHAND, specify pulmonary and systemic cardiac ventricles independent of left-right sidedness. Dev Biol 196: 228–236.
Komuro I, Izumo S 1993 Csx: a murine homeobox-containing gene specifically expressed in the developing heart. Proc Natl Acad Sci USA 90: 8145–8149.
Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP 1995 Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2–5. Gene Dev 9: 1654–1666.
Bodmer R 1993 The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development 118: 719–729.
Harvey RP 1996 NK-2 homeobox genes and heart development. Dev Biol 178: 203–216.
Schwartz RJ, Olson EN 1999 Building the heart piece by piece: modularity of cis-elements regulating Nkx2–5 transcription. Development 126: 4187–4192.
Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG 1998 Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281: 108–111.
Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD 1999 Mutations in the cardiac transcription factor NKX2. J Clin Invest 104: 1567–1573.
Ranger AM, Grusby MJ, Hodge MR, Gravallese EM, de la Brousse FC, Hoey T, Mickanin C, Baldwin HS, Glimcher LH 1998 The transcription factor NF-ATc is essential for cardiac valve formation. Nature 392: 186–190.
de la Pompa JL, Timmerman LA, Takimoto H, Yoshida H, Elia AJ, Samper E, Potter J, Wakeham A, Marengere L, Langille BL, Crabtree GR, Mak TW 1998 Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392: 182–186.
Schilham MW, Oosterwegel MA, Moerer P, Ya J, de Boer PA, van de Wetering M, Verbeek S, Lamers WH, Kruisbeek AM, Cumano A, Clevers H 1996 Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature 380: 711–714.
Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, Fairchild-Huntress V, Dixon KL, Dunmore JH, Gimbrone MA, Falb D, Huszar D 2000 A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 24: 171–174.
Potts JD, Runyan RB 1989 Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor beta. Dev Biol 134: 392–401.
Brown CB, Boyer AS, Runyan RB, Barnett JV 1999 Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science 283: 2080–2082.
Chen B, Bronson RT, Klaman LD, Hampton TG, Wang JF, Green PJ, Magnuson T, Douglas PS, Morgan JP, Neel BG 2000 Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet 24: 296–299.
Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA 1994 Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 7: 353–361.
Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins NA, Parada LF, Copeland NG 1994 Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev 8: 1019–1029.
Lakkis MM, Epstein JA 1998 Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development 125: 4359–4367.
Kaufman RL, Hartmann A, McAlister WH 1972 Family studies in congenital heart disease IV: Congenital heart disease associated with neurofibromatosis. Birth Defects: Original Articles Series VIII 92–95
Colley A, Donnai D, Evans DG 1996 Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis. Clin Genet 49: 59–64.
Lin AE, Birch PH, Korf BR, Schneider GH, Tenconi R, Niimura M, Poyhonen M, Armfield HK, Sigorini M, Virdis R, Romano C, Bonioli E, Wolkenstein P, Pivnick EK, Lawrence M, Friedman JM, and the NNFF International Database Participants 2000 Cardiovascular malformations and other cardiac abnormalities in neurofibromatosis 1 (NF1). Am J Med Genet in press
Lin CR, Kioussi C, O'Connell S, Briata P, Szeto D, Liu F, Izpisua-Belmonte JC, Rosenfeld MG 1999 Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401: 279–282.
Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF 1999 Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature 401: 276–278.
Ryan AK, Blumberg B, Rodriguez-Esteban C, Yonei-Tamura S, Tamura K, Tsukui T, de la Pena J, Sabbagh W, Greenwald J, Choe S, Norris DP, Robertson EJ, Evans RM, Rosenfeld MG, Izpisua Belmonte JC 1998 Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 394: 545–551.
Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU, Carey JC, Murray JC 1996 Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14: 392–399.
Vrancken Peeters MP, Gittenberger-de Groot AC, Mentink MM, Poelmann RE 1999 Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelial-mesenchymal transformation of the epicardium. Anat Embryol Berl 199: 367–378.
Xavier-Neto J, Shapiro MD, Houghton L, Rosenthal N 2000 Sequential programs of retinoic acid synthesis in the myocardial and epicardial layers of the developing avian heart. Dev Biol 219: 129–141.
Moore AW, McInnes L, Kreidberg J, Hastie ND, Schedl A 1999 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126: 1845–1857.
Tevosian SG, Deconinck AE, Tanaka M, Schinke M, Litovsky SH, Izumo S, Fujiwara Y, Orkin SH 2000 FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101: 729–739.
Gruber PJ, Kubalak SW, Pexieder T, Sucov HM, Evans RM, Chien KR 1996 RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. J Clin Invest 98: 1332–1343.
Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, Mark M 1994 Function of the retinoic acid receptors (RARs) during development (II). Development 120: 2749–2771.
Epstein JA 1996 Pax3, neural crest and cardiovascular development. Trends Cardiovasc Med 6: 255–261.
Epstein JA, Li J, Lang D, Chen F, Brown CB, Jin F, Lu MM, Thomas M, Liu E, Wessels A, Lo CW 2000 Migration of cardiac neural crest cells in splotch embryos. Development 127: 1869–1878.
Yanagisawa H, Hammer RE, Richardson JA, Williams SC, Clouthier DE, Yanagisawa M 1998 Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice. J Clin Invest 102: 22–33.
Kurihara Y, Kurihara H, Oda H, Maemura K, Nagai R, Ishikawa T, Yazaki Y 1995 Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. J Clin Invest 96: 293–300.
Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, de Wit D, Emoto N, Hammer RE 1998 Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125: 825–836.
Winnier GE, Kume T, Deng K, Rogers R, Bundy J, Raines C, Walter MA, Hogan BL, Conway SJ 1999 Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles. Dev Biol 213: 418–431.
Burn J 1999 Closing time for CATCH22. J Med Genet 36: 737–738.
Driscoll DA 1994 Genetic basis of DiGeorge and velocardio-facial syndromes. Curr Opin Pediat 6: 702–706.
Glover TW 1995 CATCHing a break on 22. Nat Genet 10: 257–258.
McDonald-McGinn DM, Kirschner R, Goldmuntz E, Sullivan K, Eicher P, Gerdes M, Moss E, Solot C, Wang P, Jacobs I, Handler S, Knightly C, Heher K, Wilson M, Ming JE, Grace K, Driscoll D, Pasquariello P, Randall P, Larossa D, Emanuel BS, Zackai EH 1999 The Philadelphia story: the 22q11. Genet Couns 10: 11–24.
Scambler PJ 1999 Genetics. Nature 401: 335–357.
Wilson DI, Burn J, Scambler P, Goodship J 1993 DiGeorge syndrome: part of CATCH 22. J Med Genet 30: 852–856.
Gong W, Emanuel BS, Collins J, Kim DH, Wang Z, Chen F, Zhang G, Roe B, Budarf ML 1996 A transcription map of the DiGeorge and velocardio-facial syndrome minimal critical region on 22q11. Hum Mol Genet 5: 789–800.
Sutherland HF, Kim UJ, Scambler PJ 1998 Cloning and comparative mapping of the DiGeorge syndrome critical region in the mouse. Genomics 52: 37–43.
Augusseau S, Jouk S, Jalbert P, Prieur M 1986 DiGeorge syndrome and 22q11 rearrangements. Hum Genet 74: 206
Budarf ML, Collins J, Gong W, Roe B, Wang Z, Bailey LC, Sellinger B, Michaud D, Driscoll DA, Emanuel BS 1995 Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene. Nat Genet 10: 269–278.
Demczuk S, Aledo R, Zucman J, Delattre O, Desmaze C, Dauphinot L, Jalbert P, Rouleau GA, Thomas G, Aurias A 1995 Cloning of a balanced translocation breakpoint in the DiGeorge syndrome critical region and isolation of a novel potential adhesion receptor gene in its vicinity. Hum Mol Genet 4: 551–558.
Wadey R, Daw S, Taylor C, Atif U, Kamath S, Halford S, O'Donnell H, Wilson D, Goodship J, Burn J 1995 Isolation of a gene encoding an integral membrane protein from the vicinity of a balanced translocation breakpoint associated with DiGeorge syndrome. Hum Mol Genet 4: 1027–1033.
Daw SC, Taylor C, Kraman M, Call K, Mao J, Schuffenhauer S, Meitinger T, Lipson T, Goodship J, Scambler P 1996 A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet 13: 458–460.
Gottlieb S, Driscoll DA, Punnett HH, Sellinger B, Emanuel BS, Budarf ML 1998 Characterization of 10p deletions suggests two nonoverlapping regions contribute to the DiGeorge syndrome phenotype. Am J Hum Genet 62: 495–498.
Yamagishi H, Garg V, Matsuoka R, Thomas T, Srivastava D 1999 A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283: 1158–1161.
Wadey R, McKie J, Papapetrou C, Sutherland H, Lohman F, Osinga J, Frohn I, Hofstra R, Meijers C, Amati F, Conti E, Pizzuti A, Dallapiccola B, Novelli G, Scambler P 1999 Mutations of UFD1L are not responsible for the majority of cases of DiGeorge Syndrome/velocardiofacial syndrome without deletions within chromosome 22q11. Am J Hum Genet 65: 247–249.
Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah YC, Rosenblatt HM, Bradley A, Baldini A 1999 Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401: 379–383.
Magnaghi P, Roberts C, Lorain S, Lipinski M, Scambler PJ 1998 HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3. Nat Genet 20: 74–77.
Farrell MJ, Stadt H, Wallis KT, Scambler P, Hixon RL, Wolfe R, Leatherbury L, Kirby ML 1999 HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation. Circ Res 84: 127–135.
Puech A, Saint-Jore B, Funke B, Gilbert DJ, Sirotkin H, Copeland NG, Jenkins NA, Kucherlapati R, Morrow B, Skoultchi AI 1997 Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization. Proc Natl Acad Sci USA 94: 14608–14613.
Lund J, Roe B, Chen F, Budarf M, Galili N, Riblet R, Miller RD, Emanuel BS, Reeves RH 1999 Sequence-ready physical map of the mouse chromosome 16 region with conserved synteny to the human velocardiofacial syndrome region on 22q11. Mamm Genome 10: 438–443.
Botta A, Lindsay EA, Jurecic V, Baldini A 1997 Comparative mapping of the DiGeorge syndrome region in mouse shows inconsistent gene order and differential degree of gene conservation. Mamm Genome 8: 890–895.
Galili N, Baldwin HS, Lund J, Reeves R, Gong W, Wang Z, Roe BA, Emanuel BS, Nayak S, Mickanin C, Budarf ML, Buck CA 1997 A region of mouse chromosome 16 is syntenic to the DiGeorge, velocardiofacial syndrome minimal critical region. Genome Res 7: 17–26.
Kimber WL, Hsieh P, Hirotsune S, Yuva-Paylor L, Sutherland HF, Chen A, Ruiz-Lozano P, Hoogstraten-Miller SL, Chien KR, Paylor R, Scambler PJ, Wynshaw-Boris A 1999 Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum Mol Genet 8: 2229–2237.
McQuade L, Christodoulou J, Budarf M, Sachdev R, Wilson M, Emanuel B, Colley A 1999 Patient with a 22q11. Am J Med Genet 86: 27–33.
Rizzu P, Lindsay EA, Taylor C, O'Donnell H, Levy A, Scambler P, Baldini A 1996 Cloning and comparative mapping of a gene from the commonly deleted region of DiGeorge and Velocardiofacial syndromes conserved in C. Mamm Genome 7: 639–643.
Gottlieb S, Emanuel BS, Driscoll DA, Sellinger B, Wang Z, Roe B, Budarf ML 201 1997 The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development. Am J Hum Genet 60: 1194–1201.
Heisterkamp N, Mulder MP, Langeveld A, ten Hoeve J, Wang Z, Roe BA, Groffen J 1995 Localization of the human mitochondrial citrate transporter protein gene to chromosome 22Q11 in the DiGeorge syndrome critical region. Genomics 29: 451–456.
Goldmuntz E, Wang Z, Roe BA, Budarf ML 1996 Cloning, genomic organization, and chromosomal localization of human citrate transport protein to the DiGeorge/velocardiofacial syndrome minimal critical region. Genomics 33: 271–276.
Holmes SE, Riazi MA, Gong W, McDermid HE, Sellinger BT, Hua A, Chen F, Wang Z, Zhang G, Roe B, Gonzalez I, McDonald-McGinn DM, Zackai E, Emanuel BS, Budarf ML 1997 Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation. Hum Mol Genet 6: 357–367.
Sirotkin H, Morrow B, DasGupta R, Goldberg R, Patanjali SR, Shi G, Cannizzaro L, Shprintzen R, Weissman SM, Kucherlapati R 1996 Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome. Hum Mol Genet 5: 617–624.
Pizzuti A, Novelli G, Mari A, Ratti A, Colosimo A, Amati F, Penso D, Sangiuolo F, Calabrese G, Palka G, Silani V, Gennarelli M, Mingarelli R, Scarlato G, Scambler P, Dallapiccola B 1996 Human homologue sequences to the Drosophila dishevelled segment- polarity gene are deleted in the DiGeorge syndrome. Am J Hum Genet 58: 722–729.
Pizzuti A, Novelli G, Ratti A, Amati F, Bordoni R, Mandich P, Bellone E, Conti E, Bengala M, Mari A, Silani V, Dallapiccola B 1999 Isolation and characterization of a novel transcript embedded within HIRA, a gene deleted in DiGeorge syndrome. Mol Genet Metab 67: 227–235.
Halford S, Wadey R, Roberts C, Daw SC, Whiting JA, O'Donnell H, Dunham I, Bentley D, Lindsay E, Baldini A 1993 Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease. Hum Mol Genet 2: 2099–2107.
Wilming LG, Snoeren CA, van Rijswijk A, Grosveld F, Meijers C 1997 The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients. Hum Mol Genet 6: 247–258.
Pizzuti A, Novelli G, Ratti A, Amati F, Mari A, Calabrese G, Nicolis S, Silani V, Marino B, Scarlato G, Ottolenghi S, Dallapiccola B 1997 UFD1L, a developmentally expressed ubiquitination gene, is deleted in CATCH 22 syndrome. Hum Mol Genet 6: 259–265.
Saha P, Thome KC, Yamaguchi R, Hou Z, Weremowicz S, Dutta A 209 1998 The human homolog of Saccharomyces cerevisiae CDC45. J Biol Chem 273: 18205–18209.
Sirotkin H, Morrow B, Saint-Jore B, Puech A, Das Gupta R, Patanjali SR, Skoultchi A, Weissman SM, Kucherlapati R 1997 Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics 42: 245–251.
Zieger B, Hashimoto Y, Ware J 1997 Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5′ gene with an imperfect polyadenylation signal sequence. J Clin Invest 99: 520–525.
Budarf ML, Konkle BA, Ludlow LB, Michaud D, Li M, Yamashiro DJ, McDonald-McGinn D, Zackai EH, Driscoll DA 1995 Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/velo-cardio-facial chromosomal region in 22q11. Hum Mol Genet 4: 763–766.
Chapman DL, Garvey N, Hancock S, Alexiou M, Agulnik SI, Gibson-Brown JJ, Cebra-Thomas J, Bollag RJ, Silver LM, Papaioannou VE 1996 Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev Dyn 206: 379–390.
Halford S, Wilson DI, Daw SC, Roberts C, Wadey R, Kamath S, Wickremasinghe A, Burn J, Goodship J, Mattei MG 1993 Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome. Hum Mol Genet 2: 1577–1582.
Brahe C, Bannetta P, Serra A, Arwert F 1986 The increased COMT activity in Down syndrome patients is not a consequence of dosage effect owing to location of the gene on chromosome 21: further evidence. Am J Med Genet 24: 203–204.
Sirotkin H, O'Donnell H, DasGupta R, Halford S, St Jore B, Puech A, Parimoo S, Morrow B, Skoultchi A, Weissman SM, Scambler P, Kucherlapati R 1997 Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome. Genomics 41: 75–83.
Emanuel BS, Driscoll D, Goldmuntz E, Baldwin S, Biegel J, Zackai EH, McDonald-McGinn D, Sellinger B, Gorman N, Williams S 1993 Molecular and phenotypic analysis of the chromosome 22 microdeletion syndromes. Prog Clin Biol Res 384: 207–224.
Demczuk S, Thomas G, Aurias A 1996 Isolation of a novel gene from the DiGeorge syndrome critical region with homology to Drosophila gdl and to human LAMC1 genes. Hum Mol Genet 5: 633–638.
Kurahashi H, Akagi K, Inazawa J, Ohta T, Niikawa N, Kayatani F, Sano T, Okada S, Nishisho I 1995 Isolation and characterization of a novel gene deleted in DiGeorge syndrome. Hum Mol Genet 4: 541–549.
Aubry M, Demczuk S, Desmaze C, Aikem M, Aurias A, Julien JP, Rouleau GA 1993 Isolation of a zinc finger gene consistently deleted in DiGeorge syndrome. Hum Mol Genet 2: 1583–1587.
Netter FH 1991 Heart. In: Yonkman FF(ed) The CIBA Collection of Medical Illustrations. The Hennegan Co., Cincinnati, 118–129.
Acknowledgements
Drawings shown in Figure 1 were created by Paul Schiffmacher.
Author information
Authors and Affiliations
Additional information
This work was supported by grants from the NIH (HL62974, HL61475, DK57050), the AHA, and the WW Smith Foundation.
Rights and permissions
About this article
Cite this article
Epstein, J., Buck, C. Transcriptional Regulation of Cardiac Development: Implications for Congenital Heart Disease and DiGeorge Syndrome. Pediatr Res 48, 717–724 (2000). https://doi.org/10.1203/00006450-200012000-00003
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200012000-00003
This article is cited by
-
Multipotent Progenitor Cells in Regenerative Cardiovascular Medicine
Pediatric Cardiology (2009)
-
Interventional fetal balloon valvuloplasty for congenital heart disease—current shortcomings and possible perspectives
Gynecological Surgery (2005)
-
A decade of discoveries in cardiac biology
Nature Medicine (2004)


