Neural Crest Contribution to the Cardiovascular System

  • Christopher B. Brown
  • H. Scott Baldwin
Part of the Advances in Experimental Medicine and Biology book series (volume 589)


Normal cardiovascular development requires complex remodeling of the outflow tract and pharyngeal arch arteries to create the separate pulmonic and systemic circulations. During remodeling, the outflow tract is septated to form the ascending aorta and the pulmonary trunk. The initially symmetrical pharyngeal arch arteries are remodeled to form the aortic arch, subclavian and carotid arteries. Remodeling is mediated by a population of neural crest cells arising between the midotic placode and somite four called the cardiac neural crest. Cardiac neural crest cells form smooth muscle and pericytes in the great arteries, and the neurons of cardiac innervation. In addition to the physical contribution of smooth muscle to the cardiovascular system, cardiac neural crest cells also provide signals required for the maintenance and differentiation of the other cell layers in the pharyngeal apparatus. Reciprocal signaling between the cardiac neural crest cells and cardiogenic mesoderm of the secondary heart field is required for elaboration of the conotruncus and disruption in this signaling results in primary myocardial dysfunction. Cardiovascular defects attributed to the cardiac neural crest cells may reflect either cell autonomous defects in the neural crest or defects in signaling between the neural crest and adjacent cell layers.


Aortic Arch Neural Crest Outflow Tract Neural Crest Cell Pulmonary Trunk 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Le Douarin NM. The avian embryo as a model to study the development of the neural crest: A long and still ongoing story. Mech Dev 2004; 121(9): 1089–1102.PubMedGoogle Scholar
  2. 2.
    LeDouarin NM, Kalcheim C. The Neural Crest. 2nd ed. Cambridge: Cambridge University Press, 1999.Google Scholar
  3. 3.
    Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest: Analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 1975; 34(1):125–154.PubMedGoogle Scholar
  4. 4.
    Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary septation. Science 1983; 220(4601):1059–1061.PubMedGoogle Scholar
  5. 5.
    Kirby ML, Turnage IIIrd KL, Hays BM. Characterization of conotruncal malformations following ablation of “cardiac” neural crest. Anat Rec 1985; 213(1):87–93.PubMedGoogle Scholar
  6. 6.
    Chan WY, Cheung CS, Yung KM et al. Cardiac neural crest of the mouse embryo: Axial level of origin, migratory pathway and cell autonomy of the splotch (Sp2H) mutant effect. Development 2004; 131(14):3367–3379.PubMedGoogle Scholar
  7. 7.
    Couly G, Coltey P, Eichmann A et al. The angiogenic potentials of the cephalic mesoderm and the origin of brain and head blood vessels. Mech Dev 1995; 53(1):97–112.PubMedGoogle Scholar
  8. 8.
    Waldo K, Zdanowicz M, Burch J et al. A novel role for cardiac neural crest in heart development. J Clin Invest 1999; 103(11): 1499–1507.PubMedGoogle Scholar
  9. 9.
    Waldo KL, Kirby ML. Cardiac neural crest contribution to the pulmonary artery and sixth aortic arch artery complex in chick embryos aged 6 to 18 days. Anat Rec 1993; 237(3):385–399.PubMedGoogle Scholar
  10. 10.
    Bockman DE, Kirby ML. Dependence of thymus development on derivatives of the neural crest. Science 1984; 223(4635):498–500.PubMedGoogle Scholar
  11. 11.
    Kirby ML, Waldo KL. Neural crest and cardiovascular patterning. Circ Res 1995; 77(2):211–215.PubMedGoogle Scholar
  12. 12.
    Peters-van der Sanden MJ, Luider TM, van der Kamp AW et al. Regional differences between various axial segments of the avian neural crest regarding the formation of enteric ganglia. Differentiation 1993; 53(1):17–24.PubMedGoogle Scholar
  13. 13.
    Waldo KL, Lo CW, Kirby ML. Connexin 43 expression reflects neural crest patterns during cardiovascular development. Dev Biol 1999; 208(2):307–323.PubMedGoogle Scholar
  14. 14.
    Li J, Chen F, Epstein JA. Neural crest expression of Cre recombinase directed by the proximal Pax3 promoter in transgenic mice. Genesis 2000; 26(2): 162–164.PubMedGoogle Scholar
  15. 15.
    Jiang X, Rowitch DH, Soriano P et al. Fate of the mammalian cardiac neural crest. Development 2000; 127(8):1607–1616.PubMedGoogle Scholar
  16. 16.
    Yamauchi Y, Abe K, Mantani A et al. A novel transgenic technique that allows specific marking of the neural crest cell lineage in mice. Dev Biol 1999; 212(1):191–203.PubMedGoogle Scholar
  17. 17.
    Pietri T, Eder O, Blanche M et al. The human tissue plasminogen activator-Cre mouse: A new tool for targeting specifically neural crest cells and their derivatives in vivo. Dev Biol 2003; 259(1):176–187.PubMedGoogle Scholar
  18. 18.
    Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 1999; 21(1):70–71.PubMedGoogle Scholar
  19. 19.
    Brown CB, Wenning JM, Lu MM et al. Cremediated excision of Fgf8 in the Tbx1 expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse. Dev Biol 2004; 267(1):190–202.PubMedGoogle Scholar
  20. 20.
    Poelmann RE, Lie-Venema H, Gittenberger-de Groot AC. The role of the epicardium and neural crest as extracardiac contributors to coronary vascular development. Tex Heart Inst J 2002; 29(4):255–261.PubMedGoogle Scholar
  21. 21.
    Poelmann RE, Jongbloed MR, Molin DG et al. The neural crest is contiguous with the cardiac conduction system in the mouse embryo: A role in induction? Anat Embryol (Berl) 2004; 208(5):389–393.PubMedGoogle Scholar
  22. 22.
    Stottmann RW, Choi M, Mishina Y et al. BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium. Development 2004; 131(9):2205–2218.PubMedGoogle Scholar
  23. 23.
    Waldo KL, Kumiski DH, Kirby ML. Association of the cardiac neural crest with development of the coronary arteries in the chick embryo. Anat Rec 1994; 239(3):315–331.PubMedGoogle Scholar
  24. 24.
    Harvey RP. Patterning the vertebrate heart. Nat Rev Genet 2002; 3(7):544–556.PubMedGoogle Scholar
  25. 25.
    Olson EN, Schneider MD. Sizing up the heart: Development redux in disease. Genes Dev 2003; 17(16):1937–1956.PubMedGoogle Scholar
  26. 26.
    Hutson MR, Kirby ML. Neural crest and cardiovascular development: A 20-year perspective. Birth Defects Res C Embryo Today 2003; 69(1):2–13.PubMedGoogle Scholar
  27. 27.
    Waldo K, Miyagawa-Tomita S, Kumiski D et al. Cardiac neural crest cells provide new insight into septation of the cardiac outflow tract: Aortic sac to ventricular septal closure. Dev Biol 1998; 196(2): 129–144.PubMedGoogle Scholar
  28. 28.
    Bockman DE, Redmond ME, Waldo K et al. Effect of neural crest ablation on development of the heart and arch arteries in the chick. Am J Anat 1987; 180(4):332–341.PubMedGoogle Scholar
  29. 29.
    Yelbuz TM, Waldo KL, Kumiski DH et al. Shortened outflow tract leads to altered cardiac looping after neural crest ablation. Circulation 2002; 106(4):504–510.PubMedGoogle Scholar
  30. 30.
    Nishibatake M, Kirby ML, Van Mierop LH. Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. Circulation 1987; 75(1):255–264.PubMedGoogle Scholar
  31. 31.
    Waldo KL, Kumiski D, Kirby ML. Cardiac neural crest is essential for the persistence rather than the formation of an arch artery. Dev Dyn 1996; 205(3):281–292.PubMedGoogle Scholar
  32. 32.
    Farrell M, Waldo K, Li YX et al. A novel role for cardiac neural crest in heart development. Trends Cardiovasc Med 1999; 9(7):214–220.PubMedGoogle Scholar
  33. 33.
    Farrell MJ, Burch JL, Wallis K et al. FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation. J Clin Invest 2001; 107(12): 1509–1517.PubMedGoogle Scholar
  34. 34.
    Creazzo TL, Brotto MA, Burch J. Excitation-contraction coupling in the day 15 embryonic chick heart with persistent truncus arteriosus. Pediatr Res 1997; 42(6):731–737.PubMedGoogle Scholar
  35. 35.
    Graham A. The development and evolution of the pharyngeal arches. J Anat 2001; 199 (Pt 1–2):133–141.PubMedGoogle Scholar
  36. 36.
    Bockman DE, Redmond ME, Kirby ML. Alteration of early vascular development after ablation of cranial neural crest. Anat Rec 1989; 225(3):209–217.PubMedGoogle Scholar
  37. 37.
    Etchevers HC, Vincent C, Le Douarin NM et al. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 2001; 128(7):1059–1068.PubMedGoogle Scholar
  38. 38.
    Etchevers HC, Couly G, Le Douarin NM. Morphogenesis of the branchial vascular sector. Trends Cardiovasc Med 2002; 12(7):299–304.PubMedGoogle Scholar
  39. 39.
    Hiruma T, Hirakow R. Formation of the pharyngeal arch arteries in the chick embryo. Observations of corrosion casts by scanning electron microscopy. Anat Embryol (Berl) 1995; 191(5):415–423.PubMedGoogle Scholar
  40. 40.
    Hiruma T, Nakajima Y, Nakamura H. Development of pharyngeal arch arteries in early mouse embryo. J Anat 2002; 201(1):15–29.PubMedGoogle Scholar
  41. 41.
    Webb S, Qayyum SR, Anderson RH et al. Septation and separation within the outflow tract of the developing heart. J Anat 2003; 202(4):327–342.PubMedGoogle Scholar
  42. 42.
    Ya J, Schilham MW, Clevers H et al. Animal models of congenital defects in the ventriculoarterial connection of the heart. J Mol Med 1997; 75(8):551–566.PubMedGoogle Scholar
  43. 43.
    Ya J, van den Hoff MJ, de Boer PA et al. Normal development of the outflow tract in the rat. Circ Res 1998; 82(4):464–472.PubMedGoogle Scholar
  44. 44.
    van den Hoff MJ, Kruithof BP, Moorman AF et al. Formation of myocardium after the initial development of the linear heart tube. Dev Biol 2001; 240(1):61–76.PubMedGoogle Scholar
  45. 45.
    Yang YP, Li HR, Jing Y. Septation and shortening of outflow tract in embryonic mouse heart involve changes in cardiomyocyte phenotype and alpha-SMA positive cells in the endocardium. Chin Med J (Engl) 2004; 117(8):1240–1245.PubMedGoogle Scholar
  46. 46.
    Conway SJ, Godt RE, Hatcher CJ et al. Neural crest is involved in development of abnormal myocardial function. J Mol Cell Cardiol 1997; 29(10):2675–2685.PubMedGoogle Scholar
  47. 47.
    Creazzo TL, Godt RE, Leatherbury L et al. Role of cardiac neural crest cells in cardiovascular development. Annu Rev Physiol 1998; 60:267–286.PubMedGoogle Scholar
  48. 48.
    de la Cruz MV, Sanchez Gomez C, Arteaga MM et al. Experimental study of the development of the truncus and the conus in the chick embryo. J Anat 1977; 123(3):661–686.PubMedGoogle Scholar
  49. 49.
    Zaffran S, Kelly RG, Meilhac SM et al. Right ventricular myocardium derives from the anterior heart field. Circ Res 2004; 95(3):261–268.PubMedGoogle Scholar
  50. 50.
    Kelly RG, Brown NA, Buckingham ME. The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 2001; 1(3):435–440.PubMedGoogle Scholar
  51. 51.
    Waldo KL, Kumiski DH, Wallis KT et al. Conotruncal myocardium arises from a secondary heart field. Development 2001; 128(16):3179–3188.PubMedGoogle Scholar
  52. 52.
    Abu-Issa R, Waldo K, Kirby ML. Heart fields: One, two or more? Dev Biol 2004; 272(2):281–285.PubMedGoogle Scholar
  53. 53.
    Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R et al. The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 2001; 238(1):97–109.PubMedGoogle Scholar
  54. 54.
    Yelbuz TM, Waldo KL, Zhang X et al. Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract. Dev Dyn 2003; 228(2):152–160.PubMedGoogle Scholar
  55. 55.
    Auerbach R. Analysis of the developmental effects of a lethal mutation in the house mouse. Journal of experimental zooloy 1954; 127:305–329.Google Scholar
  56. 56.
    Franz T. Persistent truncus arteriosus in the Splotch mutant mouse. Anat Embryol (Berl) 1989; 180(5):457–464.PubMedGoogle Scholar
  57. 57.
    Conway SJ, Henderson DJ, Copp AJ. Pax3 is required for cardiac neural crest migration in the mouse: Evidence from the splotch (Sp2H) mutant. Development 1997; 124(2):505–514.PubMedGoogle Scholar
  58. 58.
    Epstein JA, Li J, Lang D et al. Migration of cardiac neural crest cells in Splotch embryos. Development 2000; 127(9):1869–1878.PubMedGoogle Scholar
  59. 59.
    Epstein DJ, Vogan KJ, Trasler DG et al. A mutation within intron 3 of the Pax-3 gene produces aberrantly spliced mRNA transcripts in the splotch (Sp) mouse mutant. Proc Natl Acad Sci USA 1993; 90(2):532–536.PubMedGoogle Scholar
  60. 60.
    Epstein DJ, Vekemans M, Gros P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell 1991; 67(4):767–774.PubMedGoogle Scholar
  61. 61.
    Vogan KJ, Epstein DJ, Trasler DG et al. The splotch-delayed (Spd) mouse mutant carries a point mutation within the paired box of the Pax-3 gene. Genomics 1993; 17(2):364–369.PubMedGoogle Scholar
  62. 62.
    Epstein JA, Shapiro DN, Cheng J et al. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc Natl Acad Sci USA 1996; 93(9):4213–4218.PubMedGoogle Scholar
  63. 63.
    Li J, Liu KC, Jin F et al. Transgenic rescue of congenital heart disease and spina bifida in Splotch mice. Development 1999; 126(11):2495–2503.PubMedGoogle Scholar
  64. 64.
    Conway SJ, Bundy J, Chen J et al. Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc Res 2000; 47(2):314–328.PubMedGoogle Scholar
  65. 65.
    Lang D, Lu MM, Huang L et al. Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature 2005; 433(7028):884–887.PubMedGoogle Scholar
  66. 66.
    Asakura A, Komaki M, Rudnicki M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 2001; 68(4–5):245–253.PubMedGoogle Scholar
  67. 67.
    Seale P, Sabourin LA, Girgis-Gabardo A et al. Pax7 is required for the specification of myogenic satellite cells. Cell 2000; 102(6):777–786.PubMedGoogle Scholar
  68. 68.
    Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol 1994; 25(11):1386–1403.PubMedGoogle Scholar
  69. 69.
    Lewin GR, Barde YA. Physiology of the neurotrophins. Annu Rev Neurosci 1996; 19:289–317.PubMedGoogle Scholar
  70. 70.
    Hiltunen JO, Arumae U, Moshnyakov M et al. Expression of mRNAs for neurotrophins and their receptors in developing rat heart. Circ Res 1996; 79(5):930–939.PubMedGoogle Scholar
  71. 71.
    Scarisbrick IA, Jones EG, Isackson PJ. Coexpression of mRNAs for NGF, BDNF, and NT-3 in the cardiovascular system of the pre and postnatal rat. J Neurosci 1993; 13(3):875–893.PubMedGoogle Scholar
  72. 72.
    Donovan MJ, Hahn R, Tessarollo L et al. Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development. Nat Genet 1996; 14(2):210–213.PubMedGoogle Scholar
  73. 73.
    Youn YH, Feng J, Tessarollo L et al. Neural crest stem cell and cardiac endothelium defects in the TrkC null mouse. Mol Cell Neurosci 2003; 24(1):160–170.PubMedGoogle Scholar
  74. 74.
    Tessarollo L, Tsoulfas P, Donovan MJ et al. Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis. Proc Natl Acad Sci USA 1997; 94(26):14776–14781.PubMedGoogle Scholar
  75. 75.
    Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 2000;14(2):142–146.PubMedGoogle Scholar
  76. 76.
    Winnier GE, Kume T, Deng K et al. Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles. Dev Biol 1999;213(2):418–431.PubMedGoogle Scholar
  77. 77.
    Iida K, Koseki H, Kakinuma H et al. Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development 1997;124(22):4627–4638.PubMedGoogle Scholar
  78. 78.
    Kume T, Jiang H, Topczewska JM et al. The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Genes Dev 2001;15(18):2470–2482.PubMedGoogle Scholar
  79. 79.
    Yamagishi H, Maeda J, Hu T et al. Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer. Genes Dev 2003;17(2):269–281.PubMedGoogle Scholar
  80. 80.
    Baldini A. DiGeorge’s syndrome: A gene at last. Lancet 2003;362(9393):1342–1343.PubMedGoogle Scholar
  81. 81.
    Vitelli F, Lindsay EA, Baldini A. Genetic dissection of the DiGeorge syndrome phenotype. Cold Spring Harb Symp Quant Biol 2002;67:327–332.PubMedGoogle Scholar
  82. 82.
    Driscoll DA, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: Consistent deletions and microdeletions of 22q11. Am J Hum Genet 1992;50(5):924–933.PubMedGoogle Scholar
  83. 83.
    Driscoll DA, Salvin J, Sellinger B et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: Implications for genetic counselling and prenatal diagnosis. J Med Genet 1993;30(10):813–817.PubMedGoogle Scholar
  84. 84.
    Driscoll DA, Spinner NB, Budarf ML et al. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 1992;44(2):261–268.PubMedGoogle Scholar
  85. 85.
    Burn J, Takao A, Wilson D et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J Med Genet 1993;30(10):822–824.PubMedGoogle Scholar
  86. 86.
    Matsuoka R, Takao A, Kimura M et al. Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am J Med Genet 1994;53(3):285–289.PubMedGoogle Scholar
  87. 87.
    Goldmuntz E, Clark BJ, Mitchell LE et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998;32(2):492–498.PubMedGoogle Scholar
  88. 88.
    Lindsay EA, Botta A, Jurecic V et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 1999;401(6751):379–383.PubMedGoogle Scholar
  89. 89.
    Merscher S, Funke B, Epstein JA et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 2001;104(4):619–629.PubMedGoogle Scholar
  90. 90.
    Epstein JA. Developing models of DiGeorge syndrome. Trends Genet 2001;17(10):S13–17.PubMedGoogle Scholar
  91. 91.
    Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 2001;27(3):286–291.PubMedGoogle Scholar
  92. 92.
    Yagi H, Furutani Y, Hamada H et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 2003;362(9393):1366–1373.PubMedGoogle Scholar
  93. 93.
    Kochilas L, Merscher-Gomez S, Lu MM et al. The role of neural crest during cardiac development in a mouse model of DiGeorge syndrome. Dev Biol 2002;251(1):157–166.PubMedGoogle Scholar
  94. 94.
    Brown CB, Feiner L, Lu MM et al. PlexinA2 and semaphorin signaling during cardiac neural crest development. Development 2001;128(16):3071–3080.PubMedGoogle Scholar
  95. 95.
    Abu-Issa R, Smyth G, Smoak I et al. Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 2002;129(19):4613–4625.PubMedGoogle Scholar
  96. 96.
    Frank DU, Fotheringham LK, Brewer JA et al. An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development 2002;129(19):4591–4603.PubMedGoogle Scholar
  97. 97.
    Vitelli F, Taddei I, Morishima M et al. A genetic link between Tbx1 and fibroblast growth factor signaling. Development 2002;129(19):4605–4611.PubMedGoogle Scholar
  98. 98.
    Macatee TL, Hammond BP, Arenkiel BR et al. Ablation of specific expression domains reveals discrete functions of ectoderm-and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development 2003;130(25):6361–6374.PubMedGoogle Scholar
  99. 99.
    Hu T, Yamagishi H, Maeda J et al. Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Development 2004;131(21):5491–5502.PubMedGoogle Scholar
  100. 100.
    Xu H, Morishima M, Wylie JN et al. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development 2004;131(13):3217–3227.PubMedGoogle Scholar
  101. 101.
    Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 1953;92(2):189–217.PubMedGoogle Scholar
  102. 102.
    Wilson JG, Warkany J. Congenital anomalies of heart and great vessels in offspring of vitamin A-deficient rats. Am J Dis Child 1950;79(5):963.PubMedGoogle Scholar
  103. 103.
    Wilson JG, Warkany J. Cardiac and aortic arch anomalies in the offspring of vitamin A deficient rats correlated with similar human anomalies. Pediatrics 1950;5(4):708–725.PubMedGoogle Scholar
  104. 104.
    Niederreither K, Vermot J, Le Roux I et al. The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. Development 2003;130(11):2525–2534.PubMedGoogle Scholar
  105. 105.
    Niederreither K, Vermot J, Messaddeq N et al. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development 2001;128(7):1019–1031.PubMedGoogle Scholar
  106. 106.
    Giguere V. Retinoic acid receptors and cellular retinoid binding proteins: Complex interplay in retinoid signaling. Endocr Rev 1994;15(1):61–79.PubMedGoogle Scholar
  107. 107.
    Heyman RA, Mangelsdorf DJ, Dyck JA et al. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 1992;68(2):397–406.PubMedGoogle Scholar
  108. 108.
    Levin AA, Sturzenbecker LJ, Kazmer S et al. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 1992;355(6358):359–361.PubMedGoogle Scholar
  109. 109.
    Lohnes D, Mark M, Mendelsohn C et al. Developmental roles of the retinoic acid receptors. J Steroid Biochem Mol Biol 1995;53(1–6):475–486.PubMedGoogle Scholar
  110. 110.
    Jiang X, Choudhary B, Merki E et al. Normal fate and altered function of the cardiac neural crest cell lineage in retinoic acid receptor mutant embryos. Mech Dev 2002;117(1–2):115–122.PubMedGoogle Scholar
  111. 111.
    Brondani V, Klimkait T, Egly JM et al. Promoter of FGF8 reveals a unique regulation by unliganded RARalpha. J Mol Biol 2002;319(3):715–728.PubMedGoogle Scholar
  112. 112.
    Desai TJ, Malpel S, Flentke GR et al. Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut. Dev Biol 2004;273(2):402–415.PubMedGoogle Scholar
  113. 113.
    Lo CW, Cohen MF, Huang GY et al. Cx43 gap junction gene expression and gap junctional communication in mouse neural crest cells. Dev Genet 1997;20(2):119–132.PubMedGoogle Scholar
  114. 114.
    Reaume AG, de Sousa PA, Kulkarni S et al. Cardiac malformation in neonatal mice lacking connexin43. Science 1995;267(5205):1831–1834.PubMedGoogle Scholar
  115. 115.
    Huang GY, Wessels A, Smith BR et al. Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development. Dev Biol 1998;198(1):32–44.PubMedGoogle Scholar
  116. 116.
    Ewart JL, Cohen MF, Meyer RA et al. Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene. Development 1997;124(7):1281–1292.PubMedGoogle Scholar
  117. 117.
    Li WE, Waldo K, Linask KL et al. An essential role for connexin43 gap junctions in mouse coronary artery development. Development 2002;129(8):2031–2042.PubMedGoogle Scholar
  118. 118.
    Fredriksson L, Li H, Eriksson U. The PDGF family: Four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 2004;15(4):197–204.PubMedGoogle Scholar
  119. 119.
    Grunberg H, Truslove GM. Two closely linked genes in the mouse. Genetic Research 1960;1:69–90.Google Scholar
  120. 120.
    Orr-Urtreger A, Bedford MT, Do MS et al. Developmental expression of the alpha receptor for platelet-derived growth factor, which is deleted in the embryonic lethal Patch mutation. Development 1992;115(1):289–303.PubMedGoogle Scholar
  121. 121.
    Soriano P. The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Development 1997;124(14):2691–2700.PubMedGoogle Scholar
  122. 122.
    Tallquist MD, Soriano P. Cell autonomous requirement for PDGFRalpha in populations of cranial and cardiac neural crest cells. Development 2003;130(3):507–518.PubMedGoogle Scholar
  123. 123.
    Inoue A, Yanagisawa M, Kimura S et al. The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 1989;86(8):2863–2867.PubMedGoogle Scholar
  124. 124.
    Yanagisawa H, Hammer RE, Richardson JA et al. Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. J Clin Invest 2000;105(10):1373–1382.PubMedGoogle Scholar
  125. 125.
    Arai H, Hori S, Aramori I et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990;348(6303):730–732.PubMedGoogle Scholar
  126. 126.
    Sakurai T, Yanagisawa M, Takuwa Y et al. Cloning of a cDNA encoding a nonisopeptide-selective subtype of the endothelin receptor. Nature 1990;348(6303):732–735.PubMedGoogle Scholar
  127. 127.
    Yanagisawa H, Hammer RE, Richardson JA et al. Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice. J Clin Invest 1998;102(1):22–33.PubMedGoogle Scholar
  128. 128.
    Hogan BL. Bmps: Multifunctional regulators of mammalian embryonic development. Harvey Lect 1996;92:83–98.PubMedGoogle Scholar
  129. 129.
    Zhao GQ. Consequences of knocking out BMP signaling in the mouse. Genesis 2003;35(1):43–56.PubMedGoogle Scholar
  130. 130.
    Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113(6):685–700.PubMedGoogle Scholar
  131. 131.
    de Caestecker M. The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev 2004;15(1):1–11.PubMedGoogle Scholar
  132. 132.
    Nohe A, Keating E, Knaus P et al. Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004;16(3):291–299.PubMedGoogle Scholar
  133. 133.
    Zhang D, Schwarz EM, Rosier RN et al. ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J Bone Miner Res 2003;18(9):1593–1604.PubMedGoogle Scholar
  134. 134.
    Mishina Y, Crombie R, Bradley A et al. Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis. Dev Biol 1999;213(2):314–326.PubMedGoogle Scholar
  135. 135.
    Kallapur S, Ormsby I, Doetschman T. Strain dependency of TGFbeta1 function during embryo-genesis. Mol Reprod Dev 1999;52(4):341–349.PubMedGoogle Scholar
  136. 136.
    Proetzel G, Pawlowski SA, Wiles MV et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 1995;11(4):409–414.PubMedGoogle Scholar
  137. 137.
    Bartram U, Molin DG, Wisse LJ et al. Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice. Circulation 2001;103(22):2745–2752.PubMedGoogle Scholar
  138. 138.
    Oshima M, Oshima H, Taketo MM. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol 1996;179(1):297–302.PubMedGoogle Scholar
  139. 139.
    Larsson J, Goumans MJ, Sjostrand LJ et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J 2001;20(7):1663–1673.PubMedGoogle Scholar
  140. 140.
    Wurdak H, Ittner LM, Lang KS et al. Inactivation of TGFta signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome. Genes Dev 2005;19(5):530–535.PubMedGoogle Scholar
  141. 141.
    Ito Y, Yeo JY, Chytil A et al. Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development 2003;130(21):5269–5280.PubMedGoogle Scholar
  142. 142.
    Kaartinen V, Dudas M, Nagy A et al. Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells. Development 2004;131(14):3481–3490.PubMedGoogle Scholar
  143. 143.
    Delot EC, Bahamonde ME, Zhao M et al. BMP signaling is required for septation of the outflow tract of the mammalian heart. Development 2003;130(1):209–220.PubMedGoogle Scholar
  144. 144.
    Liu W, Selever J, Wang D et al. Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodeling. Proc Natl Acad Sci USA 2004;101(13):4489–4494.PubMedGoogle Scholar
  145. 145.
    Luo Y, Raible D, Raper JA. Collapsin: A protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 1993;75(2):217–227.PubMedGoogle Scholar
  146. 146.
    Koppel AM, Feiner L, Kobayashi H et al. A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members. Neuron 1997;19(3):531–537.PubMedGoogle Scholar
  147. 147.
    Yu HH, Kolodkin AL. Semaphorin signaling: A little less per-plexin. Neuron 1999;22(1):11–14.PubMedGoogle Scholar
  148. 148.
    Feiner L, Webber AL, Brown CB et al. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 2001;128(16):3061–3070.PubMedGoogle Scholar
  149. 149.
    Gitler AD, Lu MM, Epstein JA. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev Cell 2004;7(1):107–116.PubMedGoogle Scholar
  150. 150.
    Gu C, Yoshida Y, Livet J et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 2005;307(5707):265–268.PubMedGoogle Scholar
  151. 151.
    Capdevila J, Vogan KJ, Tabin CJ et al. Mechanisms of left-right determination in vertebrates. Cell 2000;101(1):9–21.PubMedGoogle Scholar
  152. 152.
    Franco D, Campione M. The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends Cardiovasc Med 2003;13(4):157–163.PubMedGoogle Scholar
  153. 153.
    Liu C, Liu W, Palie J et al. Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development 2002;129(21):5081–5091.PubMedGoogle Scholar
  154. 154.
    Kioussi C, Briata P, Baek SH et al. Identification of a Wnt/Dvl/beta-Catenin → Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 2002;111(5):673–685.PubMedGoogle Scholar
  155. 155.
    Hamblet NS, Lijam N, Ruiz-Lozano P et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 2002;129(24):5827–5838.PubMedGoogle Scholar
  156. 156.
    Kirby ML. Contribution of neural crest to heart and vessel morphology. In: Rosenthal RPHN, ed. Heart Development. New York: Academic Press, 1999:179–193.Google Scholar
  157. 157.
    Kirby ML. Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. Trends Cardiovasc Med 1993;3(1):18–23.Google Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Department of PediatricsVanderbilt University Medical CenterNashvilleUSA
  2. 2.Vanderbilt University Medical CenterNashvilleUSA

Personalised recommendations