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Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

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Abstract

Congenital heart defects affect approximately 1–5 % of human newborns each year, and of these cardiac defects 20–30 % are due to heart valve abnormalities. Recent literature indicates that the key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease, and therefore having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signaling pathways required for early specification and initiation of endothelial-to-mesenchymal transformation (EMT) in the cardiac cushions: BMP, TGF-β, and Notch signaling. BMPs secreted from the myocardium set up the environment for the overlying endocardium to become activated; Notch signaling initiates EMT; and both BMP and TGF-β signaling synergize with Notch to promote the transition of endothelia to mesenchyme and the mesenchymal cell invasiveness. Together, these three essential signaling pathways help form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGF-β, and Notch signaling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

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References

  1. Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900

    Article  PubMed  Google Scholar 

  2. Pierpont ME, Basson CT, Benson DW Jr, Gelb BD, Giglia TM, Goldmuntz E, McGee G, Sable CA, Srivastava D, Webb CL (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(23):3015–3038. doi:10.1161/circulationaha.106.183056

    Article  PubMed  Google Scholar 

  3. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J (2011) Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation 123(4):e18–e209. doi:10.1161/CIR.0b013e3182009701

    Article  PubMed  Google Scholar 

  4. Hinton RB Jr, Lincoln J, Deutsch GH, Osinska H, Manning PB, Benson DW, Yutzey KE (2006) Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ Res 98(11):1431–1438. doi:10.1161/01.RES.0000224114.65109.4e

    Article  PubMed  CAS  Google Scholar 

  5. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ (2001) Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 104(21):2525–2532

    Article  PubMed  CAS  Google Scholar 

  6. Rabkin-Aikawa E, Farber M, Aikawa M, Schoen FJ (2004) Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J Heart Valve Dis 13(5):841–847

    PubMed  Google Scholar 

  7. Hinton RB, Yutzey KE (2011) Heart valve structure and function in development and disease. Annu Rev Physiol 73:29–46. doi:10.1146/annurev-physiol-012110-142145

    Article  PubMed  CAS  Google Scholar 

  8. Pomerance A (1972) Pathogenesis of aortic stenosis and its relation to age. Br Heart J 34(6):569–574

    Article  PubMed  CAS  Google Scholar 

  9. Passik CS, Ackermann DM, Pluth JR, Edwards WD (1987) Temporal changes in the causes of aortic stenosis: a surgical pathologic study of 646 cases. Mayo Clin Proc 62(2):119–123

    Article  PubMed  CAS  Google Scholar 

  10. Peterson MD, Roach RM, Edwards JE (1985) Types of aortic stenosis in surgically removed valves. Arch Pathol Lab Med 109(9):829–832

    PubMed  CAS  Google Scholar 

  11. Stephan PJ, Henry AC 3rd, Hebeler RF Jr, Whiddon L, Roberts WC (1997) Comparison of age, gender, number of aortic valve cusps, concomitant coronary artery bypass grafting, and magnitude of left ventricular-systemic arterial peak systolic gradient in adults having aortic valve replacement for isolated aortic valve stenosis. Am J Cardiol 79(2):166–172

    Article  PubMed  CAS  Google Scholar 

  12. Wirrig EE, Hinton RB, Yutzey KE (2011) Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves. J Mol Cell Cardiol 50(3):561–569. doi:10.1016/j.yjmcc.2010.12.005

    Article  PubMed  CAS  Google Scholar 

  13. Lincoln J, Lange AW, Yutzey KE (2006) Hearts and bones: shared regulatory mechanisms in heart valve, cartilage, tendon, and bone development. Dev Biol 294(2):292–302. doi:10.1016/j.ydbio.2006.03.027

    Article  PubMed  CAS  Google Scholar 

  14. Sheikh AM, Livesey SA (2010) Surgical management of valve disease in the early 21st century. Clin Med 10(2):177–181

    Article  PubMed  Google Scholar 

  15. Abu-Issa R, Kirby ML (2007) Heart field: from mesoderm to heart tube. Annu Rev Cell Dev Biol 23:45–68. doi:10.1146/annurev.cellbio.23.090506.123331

    Article  PubMed  CAS  Google Scholar 

  16. Combs MD, Yutzey KE (2009) Heart valve development: regulatory networks in development and disease. Circ Res 105(5):408–421. doi:10.1161/circresaha.109.201566

    Article  PubMed  CAS  Google Scholar 

  17. Snarr BS, Kern CB, Wessels A (2008) Origin and fate of cardiac mesenchyme. Dev Dyn 237(10):2804–2819. doi:10.1002/dvdy.21725

    Article  PubMed  Google Scholar 

  18. Person AD, Klewer SE, Runyan RB (2005) Cell biology of cardiac cushion development. Int Rev Cytol 243:287–335. doi:10.1016/s0074-7696(05)43005-3

    Article  PubMed  CAS  Google Scholar 

  19. Camenisch TD, Molin DG, Person A, Runyan RB, de Groot ACG, McDonald JA, Klewer SE (2002) Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol 248(1):170–181

    Article  PubMed  CAS  Google Scholar 

  20. Schroeder JA, Jackson LF, Lee DC, Camenisch TD (2003) Form and function of developing heart valves: coordination by extracellular matrix and growth factor signaling. J Mol Med (Berl) 81(7):392–403. doi:10.1007/s00109-003-0456-5

    Article  CAS  Google Scholar 

  21. Markwald RR, Fitzharris TP, Manasek FJ (1977) Structural development of endocardial cushions. Am J Anat 148(1):85–119. doi:10.1002/aja.1001480108

    Article  PubMed  CAS  Google Scholar 

  22. Restivo A, Piacentini G, Placidi S, Saffirio C, Marino B (2006) Cardiac outflow tract: a review of some embryogenetic aspects of the conotruncal region of the heart. Anat Rec A Discov Mol Cell Evol Biol 288(9):936–943. doi:10.1002/ar.a.20367

    PubMed  Google Scholar 

  23. Hinton RB Jr, Alfieri CM, Witt SA, Glascock BJ, Khoury PR, Benson DW, Yutzey KE (2008) Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult. Am J Physiol Heart Circ Physiol 294(6):H2480–H2488. doi:10.1152/ajpheart.91431.2007

    Article  PubMed  CAS  Google Scholar 

  24. Aikawa E, Whittaker P, Farber M, Mendelson K, Padera RF, Aikawa M, Schoen FJ (2006) Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113(10):1344–1352. doi:10.1161/circulationaha.105.591768

    Article  PubMed  Google Scholar 

  25. Butcher JT, Markwald RR (2007) Valvulogenesis: the moving target. Philos Trans R Soc Lond B Biol Sci 362(1484):1489–1503. doi:10.1098/rstb.2007.2130

    Article  PubMed  CAS  Google Scholar 

  26. Kruithof BP, Krawitz SA, Gaussin V (2007) Atrioventricular valve development during late embryonic and postnatal stages involves condensation and extracellular matrix remodeling. Dev Biol 302(1):208–217. doi:10.1016/j.ydbio.2006.09.024

    Article  PubMed  CAS  Google Scholar 

  27. Sacks MS, Yoganathan AP (2007) Heart valve function: a biomechanical perspective. Philos Trans R Soc Lond B Biol Sci 362(1484):1369–1391. doi:10.1098/rstb.2007.2122

    Article  PubMed  Google Scholar 

  28. Vesely I (1998) The role of elastin in aortic valve mechanics. J Biomech 31(2):115–123

    Article  PubMed  CAS  Google Scholar 

  29. de Lange FJ, Moorman AF, Anderson RH, Manner J, Soufan AT, de Gier-de VC, Schneider MD, Webb S, van den Hoff MJ, Christoffels VM (2004) Lineage and morphogenetic analysis of the cardiac valves. Circ Res 95(6):645–654. doi:10.1161/01.RES.0000141429.13560.cb

    Article  PubMed  CAS  Google Scholar 

  30. Lincoln J, Alfieri CM, Yutzey KE (2004) Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos. Dev Dyn 230(2):239–250. doi:10.1002/dvdy.20051

    Article  PubMed  CAS  Google Scholar 

  31. Wessels A, van den Hoff MJ, Adamo RF, Phelps AL, Lockhart MM, Sauls K, Briggs LE, Norris RA, van Wijk B, Perez-Pomares JM, Dettman RW, Burch JB (2012) Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart. Dev Biol 366(2):111–124. doi:10.1016/j.ydbio.2012.04.020

    Article  PubMed  CAS  Google Scholar 

  32. Liu AC, Joag VR, Gotlieb AI (2007) The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol 171(5):1407–1418. doi:10.2353/ajpath.2007.070251

    Article  PubMed  CAS  Google Scholar 

  33. Xiao H, Zhang YY (2008) Understanding the role of transforming growth factor-beta signalling in the heart: overview of studies using genetic mouse models. Clin Exp Pharmacol Physiol 35(3):335–341. doi:10.1111/j.1440-1681.2007.04876.x

    Article  PubMed  CAS  Google Scholar 

  34. Conway SJ, Doetschman T, Azhar M (2011) The inter-relationship of periostin, TGF beta, and BMP in heart valve development and valvular heart diseases. ScientificWorldJournal 11:1509–1524. doi:10.1100/tsw.2011.132

    Article  PubMed  CAS  Google Scholar 

  35. Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19(1):128–139. doi:10.1038/cr.2008.328

    Article  PubMed  CAS  Google Scholar 

  36. Stevens MV, Parker P, Vaillancourt RR, Camenisch TD (2006) MEKK4 regulates developmental EMT in the embryonic heart. Dev Dyn 235(10):2761–2770. doi:10.1002/dvdy.20922

    Article  PubMed  CAS  Google Scholar 

  37. Sakabe M, Ikeda K, Nakatani K, Kawada N, Imanaka-Yoshida K, Yoshida T, Yamagishi T, Nakajima Y (2006) Rho kinases regulate endothelial invasion and migration during valvuloseptal endocardial cushion tissue formation. Dev Dyn 235(1):94–104. doi:10.1002/dvdy.20648

    Article  PubMed  CAS  Google Scholar 

  38. Feng Q, Di R, Tao F, Chang Z, Lu S, Fan W, Shan C, Li X, Yang Z (2010) PDK1 regulates vascular remodeling and promotes epithelial-mesenchymal transition in cardiac development. Mol Cell Biol 30(14):3711–3721. doi:10.1128/mcb.00420-10

    Article  PubMed  CAS  Google Scholar 

  39. Zhu HJ, Burgess AW (2001) Regulation of transforming growth factor-beta signaling. Mol Cell Biol Res Commun 4(6):321–330. doi:10.1006/mcbr.2001.0301

    Article  PubMed  CAS  Google Scholar 

  40. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389(6651):622–626. doi:10.1038/39355

    Article  PubMed  CAS  Google Scholar 

  41. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389(6651):631–635. doi:10.1038/39369

    Article  PubMed  CAS  Google Scholar 

  42. Park SH (2005) Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 38(1):9–16

    Article  PubMed  Google Scholar 

  43. Ma L, Lu MF, Schwartz RJ, Martin JF (2005) Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132(24):5601–5611. doi:10.1242/dev.02156

    Article  PubMed  CAS  Google Scholar 

  44. Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, Hogan BL (2003) An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev 17(19):2362–2367. doi:10.1101/gad.1124803

    Article  PubMed  CAS  Google Scholar 

  45. Solloway MJ, Robertson EJ (1999) Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup. Development 126(8):1753–1768

    PubMed  CAS  Google Scholar 

  46. Kim RY, Robertson EJ, Solloway MJ (2001) Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. Dev Biol 235(2):449–466. doi:10.1006/dbio.2001.0284

    Article  PubMed  CAS  Google Scholar 

  47. Somi S, Buffing AA, Moorman AF, Van Den Hoff MJ (2004) Dynamic patterns of expression of BMP isoforms 2, 4, 5, 6, and 7 during chicken heart development. Anat Rec A Discov Mol Cell Evol Biol 279(1):636–651. doi:10.1002/ar.a.20031

    Article  PubMed  CAS  Google Scholar 

  48. Somi S, Buffing AA, Moorman AF, Van Den Hoff MJ (2004) Expression of bone morphogenetic protein-10 mRNA during chicken heart development. Anat Rec A Discov Mol Cell Evol Biol 279(1):579–582. doi:10.1002/ar.a.20052

    Article  PubMed  CAS  Google Scholar 

  49. Wang J, Sridurongrit S, Dudas M, Thomas P, Nagy A, Schneider MD, Epstein JA, Kaartinen V (2005) Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart. Dev Biol 286(1):299–310. doi:10.1016/j.ydbio.2005.07.035

    Article  PubMed  CAS  Google Scholar 

  50. Dewulf N, Verschueren K, Lonnoy O, Moren A, Grimsby S, Vande Spiegle K, Miyazono K, Huylebroeck D, Ten Dijke P (1995) Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis. Endocrinology 136(6):2652–2663

    Article  PubMed  CAS  Google Scholar 

  51. Roelen BA, Goumans MJ, van Rooijen MA, Mummery CL (1997) Differential expression of BMP receptors in early mouse development. Int J Dev Biol 41(4):541–549

    PubMed  CAS  Google Scholar 

  52. Yamagishi T, Nakajima Y, Miyazono K, Nakamura H (1999) Bone morphogenetic protein-2 acts synergistically with transforming growth factor-beta3 during endothelial-mesenchymal transformation in the developing chick heart. J Cell Physiol 180(1):35–45. doi:10.1002/(sici)1097-4652(199907)180:1<35:aid-jcp4>3.0.co;2-r

    Article  PubMed  CAS  Google Scholar 

  53. Zhang H, Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122(10):2977–2986

    PubMed  CAS  Google Scholar 

  54. Sugi Y, Yamamura H, Okagawa H, Markwald RR (2004) Bone morphogenetic protein-2 can mediate myocardial regulation of atrioventricular cushion mesenchymal cell formation in mice. Dev Biol 269(2):505–518. doi:10.1016/j.ydbio.2004.01.045

    Article  PubMed  CAS  Google Scholar 

  55. Luna-Zurita L, Prados B, Grego-Bessa J, Luxan G, del Monte G, Benguria A, Adams RH, Perez-Pomares JM, de la Pompa JL (2010) Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation. J Clin Invest 120(10):3493–3507. doi:10.1172/jci42666

    Article  PubMed  CAS  Google Scholar 

  56. McCulley DJ, Kang JO, Martin JF, Black BL (2008) BMP4 is required in the anterior heart field and its derivatives for endocardial cushion remodeling, outflow tract septation, and semilunar valve development. Dev Dyn 237(11):3200–3209. doi:10.1002/dvdy.21743

    Article  PubMed  CAS  Google Scholar 

  57. Uchimura T, Komatsu Y, Tanaka M, McCann KL, Mishina Y (2009) Bmp2 and Bmp4 genetically interact to support multiple aspects of mouse development including functional heart development. Genesis 47(6):374–384. doi:10.1002/dvg.20511

    Article  PubMed  CAS  Google Scholar 

  58. Kingsley DM, Bland AE, Grubber JM, Marker PC, Russell LB, Copeland NG, Jenkins NA (1992) The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Cell 71(3):399–410

    Article  PubMed  CAS  Google Scholar 

  59. Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, Robertson EJ (1998) Mice lacking Bmp6 function. Dev Genet 22(4):321–339. doi:10.1002/(sici)1520-6408(1998)22:4<321:aid-dvg3>3.0.co;2-8

    Article  PubMed  CAS  Google Scholar 

  60. Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9(22):2795–2807

    Article  PubMed  CAS  Google Scholar 

  61. Gu Z, Reynolds EM, Song J, Lei H, Feijen A, Yu L, He W, MacLaughlin DT, van den Eijnden-van Raaij J, Donahoe PK, Li E (1999) The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development 126(11):2551–2561

    PubMed  CAS  Google Scholar 

  62. Mishina Y, Suzuki A, Ueno N, Behringer RR (1995) Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev 9(24):3027–3037

    Article  PubMed  CAS  Google Scholar 

  63. Beppu H, Kawabata M, Hamamoto T, Chytil A, Minowa O, Noda T, Miyazono K (2000) BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol 221(1):249–258. doi:10.1006/dbio.2000.9670

    Article  PubMed  CAS  Google Scholar 

  64. Song L, Fassler R, Mishina Y, Jiao K, Baldwin HS (2007) Essential functions of Alk3 during AV cushion morphogenesis in mouse embryonic hearts. Dev Biol 301(1):276–286. doi:10.1016/j.ydbio.2006.08.004

    Article  PubMed  CAS  Google Scholar 

  65. Gaussin V, Van de Putte T, Mishina Y, Hanks MC, Zwijsen A, Huylebroeck D, Behringer RR, Schneider MD (2002) Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci USA 99(5):2878–2883. doi:10.1073/pnas.042390499

    Article  PubMed  CAS  Google Scholar 

  66. Gaussin V, Morley GE, Cox L, Zwijsen A, Vance KM, Emile L, Tian Y, Liu J, Hong C, Myers D, Conway SJ, Depre C, Mishina Y, Behringer RR, Hanks MC, Schneider MD, Huylebroeck D, Fishman GI, Burch JB, Vatner SF (2005) Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus. Circ Res 97(3):219–226. doi:10.1161/01.res.0000177862.85474.63

    Article  PubMed  CAS  Google Scholar 

  67. Delot EC, Bahamonde ME, Zhao M, Lyons KM (2003) BMP signaling is required for septation of the outflow tract of the mammalian heart. Development 130(1):209–220

    Article  PubMed  CAS  Google Scholar 

  68. Kruithof BP, Duim SN, Moerkamp AT, Goumans MJ (2012) TGFbeta and BMP signaling in cardiac cushion formation: lessons from mice and chicken. Differentiation. doi:10.1016/j.diff.2012.04.003

    PubMed  Google Scholar 

  69. Beppu H, Malhotra R, Beppu Y, Lepore JJ, Parmacek MS, Bloch KD (2009) BMP type II receptor regulates positioning of outflow tract and remodeling of atrioventricular cushion during cardiogenesis. Dev Biol 331(2):167–175. doi:10.1016/j.ydbio.2009.04.032

    Article  PubMed  CAS  Google Scholar 

  70. Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS (2001) Bone formation and inflammation in cardiac valves. Circulation 103(11):1522–1528

    Article  PubMed  Google Scholar 

  71. Kaden JJ, Bickelhaupt S, Grobholz R, Vahl CF, Hagl S, Brueckmann M, Haase KK, Dempfle CE, Borggrefe M (2004) Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis 13(4):560–566

    PubMed  Google Scholar 

  72. Ankeny RF, Thourani VH, Weiss D, Vega JD, Taylor WR, Nerem RM, Jo H (2011) Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves–association with low BMP antagonists and SMAD6. PLoS ONE 6(6):e20969. doi:10.1371/journal.pone.0020969

    Article  PubMed  CAS  Google Scholar 

  73. Yamagishi T, Ando K, Nakamura H (2009) Roles of TGFbeta and BMP during valvulo-septal endocardial cushion formation. Anat Sci Int 84(3):77–87. doi:10.1007/s12565-009-0027-0

    Article  PubMed  CAS  Google Scholar 

  74. 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(2):392–401

    Article  PubMed  CAS  Google Scholar 

  75. Akhurst RJ, Lehnert SA, Faissner A, Duffie E (1990) TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis. Development 108(4):645–656

    PubMed  CAS  Google Scholar 

  76. Molin DG, Bartram U, Van der Heiden K, Van Iperen L, Speer CP, Hierck BP, Poelmann RE, Gittenberger-de-Groot AC (2003) Expression patterns of Tgfbeta1-3 associate with myocardialisation of the outflow tract and the development of the epicardium and the fibrous heart skeleton. Dev Dyn 227(3):431–444. doi:10.1002/dvdy.10314

    Article  PubMed  CAS  Google Scholar 

  77. Mariano JM, Montuenga LM, Prentice MA, Cuttitta F, Jakowlew SB (1998) Concurrent and distinct transcription and translation of transforming growth factor-beta type I and type II receptors in rodent embryogenesis. Int J Dev Biol 42(8):1125–1136

    PubMed  CAS  Google Scholar 

  78. Mummery CL (2001) Transforming growth factor beta and mouse development. Microsc Res Tech 52(4):374–386. doi:10.1002/1097-0029(20010215)52:4<374:aid-jemt1022>3.0.co;2-8

    Article  PubMed  CAS  Google Scholar 

  79. Seki T, Hong KH, Oh SP (2006) Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab Invest 86(2):116–129. doi:10.1038/labinvest.3700376

    Article  PubMed  CAS  Google Scholar 

  80. Roelen BA, van Rooijen MA, Mummery CL (1997) Expression of ALK-1, a type 1 serine/threonine kinase receptor, coincides with sites of vasculogenesis and angiogenesis in early mouse development. Dev Dyn 209(4):418–430. doi:10.1002/(sici)1097-0177(199708)209:4<418:aid-aja9>3.0.co;2-l

    Article  PubMed  CAS  Google Scholar 

  81. Stenvers KL, Tursky ML, Harder KW, Kountouri N, Amatayakul-Chantler S, Grail D, Small C, Weinberg RA, Sizeland AM, Zhu HJ (2003) Heart and liver defects and reduced transforming growth factor beta2 sensitivity in transforming growth factor beta type III receptor-deficient embryos. Mol Cell Biol 23(12):4371–4385

    Article  PubMed  CAS  Google Scholar 

  82. Qu R, Silver MM, Letarte M (1998) Distribution of endoglin in early human development reveals high levels on endocardial cushion tissue mesenchyme during valve formation. Cell Tissue Res 292(2):333–343

    Article  PubMed  CAS  Google Scholar 

  83. Potts JD, Dagle JM, Walder JA, Weeks DL, Runyan RB (1991) Epithelial-mesenchymal transformation of embryonic cardiac endothelial cells is inhibited by a modified antisense oligodeoxynucleotide to transforming growth factor beta 3. Proc Natl Acad Sci USA 88(4):1516–1520

    Article  PubMed  CAS  Google Scholar 

  84. Ramsdell AF, Markwald RR (1997) Induction of endocardial cushion tissue in the avian heart is regulated, in part, by TGFbeta-3-mediated autocrine signaling. Dev Biol 188(1):64–74. doi:10.1006/dbio.1997.8637

    Article  PubMed  CAS  Google Scholar 

  85. Boyer AS, Ayerinskas II, Vincent EB, McKinney LA, Weeks DL, Runyan RB (1999) TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol 208(2):530–545. doi:10.1006/dbio.1999.9211

    Article  PubMed  CAS  Google Scholar 

  86. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121(6):1845–1854

    PubMed  CAS  Google Scholar 

  87. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699. doi:10.1038/359693a0

    Article  PubMed  CAS  Google Scholar 

  88. Letterio JJ, Geiser AG, Kulkarni AB, Roche NS, Sporn MB, Roberts AB (1994) Maternal rescue of transforming growth factor-beta 1 null mice. Science 264(5167):1936–1938

    Article  PubMed  CAS  Google Scholar 

  89. Sanford LP, Ormsby I, de Groot ACG, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124(13):2659–2670

    PubMed  CAS  Google Scholar 

  90. Bartram U, Molin DG, Wisse LJ, Mohamad A, Sanford LP, Doetschman T, Speer CP, Poelmann RE, de Groot ACG (2001) 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 103(22):2745–2752

    Article  PubMed  CAS  Google Scholar 

  91. Azhar M, Runyan RB, Gard C, Sanford LP, Miller ML, Andringa A, Pawlowski S, Rajan S, Doetschman T (2009) Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development. Dev Dyn 238(2):431–442. doi:10.1002/dvdy.21854

    Article  PubMed  CAS  Google Scholar 

  92. Azhar M, Brown K, Gard C, Chen H, Rajan S, Elliott DA, Stevens MV, Camenisch TD, Conway SJ, Doetschman T (2011) Transforming growth factor Beta2 is required for valve remodeling during heart development. Dev Dyn 240(9):2127–2141. doi:10.1002/dvdy.22702

    Article  PubMed  CAS  Google Scholar 

  93. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11(4):415–421. doi:10.1038/ng1295-415

    Article  PubMed  CAS  Google Scholar 

  94. Larsson J, Goumans MJ, Sjostrand LJ, van Rooijen MA, Ward D, Leveen P, Xu X, ten Dijke P, Mummery CL, Karlsson S (2001) Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J 20(7):1663–1673. doi:10.1093/emboj/20.7.1663

    Article  PubMed  CAS  Google Scholar 

  95. Oshima M, Oshima H, Taketo MM (1996) TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol 179(1):297–302. doi:10.1006/dbio.1996.0259

    Article  PubMed  CAS  Google Scholar 

  96. Carvalho RL, Itoh F, Goumans MJ, Lebrin F, Kato M, Takahashi S, Ema M, Itoh S, van Rooijen M, Bertolino P, Ten Dijke P, Mummery CL (2007) Compensatory signalling induced in the yolk sac vasculature by deletion of TGFbeta receptors in mice. J Cell Sci 120(Pt 24):4269–4277. doi:10.1242/jcs.013169

    Article  PubMed  CAS  Google Scholar 

  97. Sridurongrit S, Larsson J, Schwartz R, Ruiz-Lozano P, Kaartinen V (2008) Signaling via the Tgf-beta type I receptor Alk5 in heart development. Dev Biol 322(1):208–218. doi:10.1016/j.ydbio.2008.07.038

    Article  PubMed  CAS  Google Scholar 

  98. Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E (2000) Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97(6):2626–2631

    Article  PubMed  CAS  Google Scholar 

  99. Jiao K, Langworthy M, Batts L, Brown CB, Moses HL, Baldwin HS (2006) Tgfbeta signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development. Development 133(22):4585–4593. doi:10.1242/dev.02597

    Article  PubMed  CAS  Google Scholar 

  100. Robson A, Allinson KR, Anderson RH, Henderson DJ, Arthur HM (2010) The TGFbeta type II receptor plays a critical role in the endothelial cells during cardiac development. Dev Dyn 239(9):2435–2442. doi:10.1002/dvdy.22376

    Article  PubMed  CAS  Google Scholar 

  101. Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, Burn J, Diamond AG (2000) Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 217(1):42–53. doi:10.1006/dbio.1999.9534

    Article  PubMed  CAS  Google Scholar 

  102. Bourdeau A, Dumont DJ, Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 104(10):1343–1351. doi:10.1172/jci8088

    Article  PubMed  CAS  Google Scholar 

  103. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in mice lacking endoglin. Science 284(5419):1534–1537

    Article  PubMed  CAS  Google Scholar 

  104. Compton LA, Potash DA, Brown CB, Barnett JV (2007) Coronary vessel development is dependent on the type III transforming growth factor beta receptor. Circ Res 101(8):784–791. doi:10.1161/circresaha.107.152082

    Article  PubMed  CAS  Google Scholar 

  105. Rosenkranz S (2004) TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 63(3):423–432. doi:10.1016/j.cardiores.2004.04.030

    Article  PubMed  CAS  Google Scholar 

  106. Walker GA, Masters KS, Shah DN, Anseth KS, Leinwand LA (2004) Valvular myofibroblast activation by transforming growth factor-beta: implications for pathological extracellular matrix remodeling in heart valve disease. Circ Res 95(3):253–260. doi:10.1161/01.RES.0000136520.07995.aa

    Article  PubMed  CAS  Google Scholar 

  107. Liu AC, Gotlieb AI (2008) Transforming growth factor-beta regulates in vitro heart valve repair by activated valve interstitial cells. Am J Pathol 173(5):1275–1285. doi:10.2353/ajpath.2008.080365

    Article  PubMed  CAS  Google Scholar 

  108. Jian B, Narula N, Li QY, Mohler ER 3rd, Levy RJ (2003) Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg 75(2):457–465 (discussion 465–456)

    Google Scholar 

  109. Hulin A, Deroanne CF, Lambert CA, Dumont B, Castronovo V, Defraigne JO, Nusgens BV, Radermecker MA, Colige AC (2012) Metallothionein-dependent up-regulation of TGF-beta2 participates in the remodelling of the myxomatous mitral valve. Cardiovasc Res 93(3):480–489. doi:10.1093/cvr/cvr337

    Article  PubMed  CAS  Google Scholar 

  110. Girdauskas E, Schulz S, Borger MA, Mierzwa M, Kuntze T (2011) Transforming growth factor-beta receptor type II mutation in a patient with bicuspid aortic valve disease and intraoperative aortic dissection. Ann Thorac Surg 91(5):e70–e71. doi:10.1016/j.athoracsur.2010.12.060

    Article  PubMed  Google Scholar 

  111. Attaran S, Sherwood R, Dastidar MG, El-Gamel A (2010) Identification of low circulatory transforming growth factor beta-1 in patients with degenerative heart valve disease. Interact Cardiovasc Thorac Surg 11(6):791–793. doi:10.1510/icvts.2010.244384

    Article  PubMed  Google Scholar 

  112. Goumans MJ, Mummery C (2000) Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol 44(3):253–265

    PubMed  CAS  Google Scholar 

  113. Zhu Y, Richardson JA, Parada LF, Graff JM (1998) Smad3 mutant mice develop metastatic colorectal cancer. Cell 94(6):703–714

    Article  PubMed  CAS  Google Scholar 

  114. Datto MB, Frederick JP, Pan L, Borton AJ, Zhuang Y, Wang XF (1999) Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol 19(4):2495–2504

    PubMed  CAS  Google Scholar 

  115. Hester M, Thompson JC, Mills J, Liu Y, El-Hodiri HM, Weinstein M (2005) Smad1 and Smad8 function similarly in mammalian central nervous system development. Mol Cell Biol 25(11):4683–4692. doi:10.1128/mcb.25.11.4683-4692.2005

    Article  PubMed  CAS  Google Scholar 

  116. Lechleider RJ, Ryan JL, Garrett L, Eng C, Deng C, Wynshaw-Boris A, Roberts AB (2001) Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion. Dev Biol 240(1):157–167. doi:10.1006/dbio.2001.0469

    Article  PubMed  CAS  Google Scholar 

  117. Tremblay KD, Dunn NR, Robertson EJ (2001) Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation. Development 128(18):3609–3621

    PubMed  CAS  Google Scholar 

  118. Weinstein M, Yang X, Li C, Xu X, Gotay J, Deng CX (1998) Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. Proc Natl Acad Sci USA 95(16):9378–9383

    Article  PubMed  CAS  Google Scholar 

  119. Nomura M, Li E (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393(6687):786–790. doi:10.1038/31693

    Article  PubMed  CAS  Google Scholar 

  120. Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE, Rossant J, Mak TW (1998) The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 12(1):107–119

    Article  PubMed  CAS  Google Scholar 

  121. Yang X, Li C, Xu X, Deng C (1998) The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci USA 95(7):3667–3672

    Article  PubMed  CAS  Google Scholar 

  122. Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A (1999) Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development 126(8):1631–1642

    PubMed  CAS  Google Scholar 

  123. Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, Fairchild-Huntress V, Dixon KL, Dunmore JH, Gimbrone MA Jr, Falb D, Huszar D (2000) A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 24(2):171–174. doi:10.1038/72835

    Article  PubMed  CAS  Google Scholar 

  124. Chen Q, Chen H, Zheng D, Kuang C, Fang H, Zou B, Zhu W, Bu G, Jin T, Wang Z, Zhang X, Chen J, Field LJ, Rubart M, Shou W, Chen Y (2009) Smad7 is required for the development and function of the heart. J Biol Chem 284(1):292–300. doi:10.1074/jbc.M807233200

    Article  PubMed  CAS  Google Scholar 

  125. Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE (2011) Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development [corrected]. Proc Natl Acad Sci USA 108(10):4006–4011. doi:10.1073/pnas.1019025108

    Article  PubMed  CAS  Google Scholar 

  126. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5(2):207–216. doi:S1097-2765(00)80417-7

    Article  PubMed  CAS  Google Scholar 

  127. Wen C, Metzstein MM, Greenwald I (1997) SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling. Development 124(23):4759–4767

    PubMed  CAS  Google Scholar 

  128. Parks AL, Klueg KM, Stout JR, Muskavitch MA (2000) Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127(7):1373–1385

    PubMed  CAS  Google Scholar 

  129. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398(6727):518–522. doi:10.1038/19083

    Article  PubMed  CAS  Google Scholar 

  130. Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C (2002) Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 21(20):5408–5416

    Article  PubMed  CAS  Google Scholar 

  131. Kurooka H, Kuroda K, Honjo T (1998) Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. Nucleic Acids Res 26(23):5448–5455

    Article  PubMed  CAS  Google Scholar 

  132. Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (2001) The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity. Mech Dev 104(1–2):3–20

    Article  PubMed  CAS  Google Scholar 

  133. Ong CT, Cheng HT, Chang LW, Ohtsuka T, Kageyama R, Stormo GD, Kopan R (2006) Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability. J Biol Chem 281(8):5106–5119. doi:10.1074/jbc.M506108200

    Article  PubMed  CAS  Google Scholar 

  134. Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD (1996) Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 16(3):952–959

    PubMed  CAS  Google Scholar 

  135. Wu L, Sun T, Kobayashi K, Gao P, Griffin JD (2002) Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol Cell Biol 22(21):7688–7700

    Article  PubMed  CAS  Google Scholar 

  136. Davis RL, Turner DL (2001) Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene 20(58):8342–8357. doi:10.1038/sj.onc.1205094

    Article  PubMed  CAS  Google Scholar 

  137. Iso T, Chung G, Hamamori Y, Kedes L (2002) HERP1 is a cell type-specific primary target of Notch. J Biol Chem 277(8):6598–6607. doi:10.1074/jbc.M110495200

    Article  PubMed  CAS  Google Scholar 

  138. Noseda M, Fu Y, Niessen K, Wong F, Chang L, McLean G, Karsan A (2006) Smooth Muscle alpha-actin is a direct target of Notch/CSL. Circ Res 98(12):1468–1470. doi:10.1161/01.res.0000229683.81357.26

    Article  PubMed  CAS  Google Scholar 

  139. Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, Karsan A (2008) Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol 182(2):315–325. doi:10.1083/jcb.200710067

    Article  PubMed  CAS  Google Scholar 

  140. Fu Y, Chang A, Chang L, Niessen K, Eapen S, Setiadi A, Karsan A (2009) Differential regulation of transforming growth factor beta signaling pathways by Notch in human endothelial cells. J Biol Chem 284(29):19452–19462. doi:10.1074/jbc.M109.011833

    Article  PubMed  CAS  Google Scholar 

  141. Fu Y, Chang AC, Fournier M, Chang L, Niessen K, Karsan A (2011) RUNX3 maintains the mesenchymal phenotype after termination of the Notch signal. J Biol Chem 286(13):11803–11813. doi:10.1074/jbc.M111.222331

    Article  PubMed  CAS  Google Scholar 

  142. Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138(17):3593–3612. doi:10.1242/dev.063610

    Article  PubMed  CAS  Google Scholar 

  143. Iso T, Hamamori Y, Kedes L (2003) Notch signaling in vascular development. Arterioscler Thromb Vasc Biol 23(4):543–553. doi:10.1161/01.atv.0000060892.81529.8f

    Article  PubMed  CAS  Google Scholar 

  144. Liu J, Sato C, Cerletti M, Wagers A (2010) Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr Top Dev Biol 92:367–409. doi:10.1016/s0070-2153(10)92012-7

    Article  PubMed  CAS  Google Scholar 

  145. Bigas A, Robert-Moreno A, Espinosa L (2010) The Notch pathway in the developing hematopoietic system. Int J Dev Biol 54(6–7):1175–1188. doi:10.1387/ijdb.093049ab

    Article  PubMed  CAS  Google Scholar 

  146. Lewis J, Hanisch A, Holder M (2009) Notch signaling, the segmentation clock, and the patterning of vertebrate somites. J Biol 8(4):44. doi:10.1186/jbiol145

    Article  PubMed  CAS  Google Scholar 

  147. Williams R, Lendahl U, Lardelli M (1995) Complementary and combinatorial patterns of Notch gene family expression during early mouse development. Mech Dev 53(3):357–368

    Article  PubMed  CAS  Google Scholar 

  148. Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J, Aranda S, Palomo S, McCormick F, Izpisua-Belmonte JC, de la Pompa JL (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18(1):99–115. doi:10.1101/gad.276304

    Article  PubMed  CAS  Google Scholar 

  149. Loomes KM, Taichman DB, Glover CL, Williams PT, Markowitz JE, Piccoli DA, Baldwin HS, Oakey RJ (2002) Characterization of Notch receptor expression in the developing mammalian heart and liver. Am J Med Genet 112(2):181–189. doi:10.1002/ajmg.10592

    Article  PubMed  Google Scholar 

  150. Varadkar P, Kraman M, Despres D, Ma G, Lozier J, McCright B (2008) Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells. Dev Dyn 237(4):1144–1152. doi:10.1002/dvdy.21502

    Article  PubMed  CAS  Google Scholar 

  151. Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, Karsan A (2004) Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol Cell Biol 24(20):8813–8822. doi:10.1128/mcb.24.20.8813-8822.2004

    Article  PubMed  CAS  Google Scholar 

  152. Loomes KM, Underkoffler LA, Morabito J, Gottlieb S, Piccoli DA, Spinner NB, Baldwin HS, Oakey RJ (1999) The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome. Hum Mol Genet 8(13):2443–2449

    Article  PubMed  CAS  Google Scholar 

  153. van den Akker NM, Molin DG, Peters PP, Maas S, Wisse LJ, van Brempt R, van Munsteren CJ, Bartelings MM, Poelmann RE, Carmeliet P, de Groot ACG (2007) Tetralogy of Fallot and alterations in vascular endothelial growth factor-A signaling and notch signaling in mouse embryos solely expressing the VEGF120 isoform. Circ Res 100(6):842–849. doi:10.1161/01.res.0000261656.04773.39

    Article  PubMed  CAS  Google Scholar 

  154. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J (2004) Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 18(20):2474–2478. doi:10.1101/gad.1239004

    Article  PubMed  CAS  Google Scholar 

  155. Benedito R, Duarte A (2005) Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles. Gene Expr Patterns 5(6):750–755. doi:10.1016/j.modgep.2005.04.004

    Article  PubMed  CAS  Google Scholar 

  156. Leimeister C, Externbrink A, Klamt B, Gessler M (1999) Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis. Mech Dev 85(1–2):173–177

    Article  PubMed  CAS  Google Scholar 

  157. Oka C, Nakano T, Wakeham A, de la Pompa JL, Mori C, Sakai T, Okazaki S, Kawaichi M, Shiota K, Mak TW, Honjo T (1995) Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development 121(10):3291–3301

    PubMed  CAS  Google Scholar 

  158. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T (2004) Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 18(20):2469–2473. doi:10.1101/gad.1239204

    Article  PubMed  CAS  Google Scholar 

  159. High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci USA 105(6):1955–1959. doi:10.1073/pnas.0709663105

    Article  PubMed  CAS  Google Scholar 

  160. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14(11):1343–1352

    PubMed  CAS  Google Scholar 

  161. Grego-Bessa J, Luna-Zurita L, del Monte G, Bolos V, Melgar P, Arandilla A, Garratt AN, Zang H, Mukouyama YS, Chen H, Shou W, Ballestar E, Esteller M, Rojas A, Perez-Pomares JM, de la Pompa JL (2007) Notch signaling is essential for ventricular chamber development. Dev Cell 12(3):415–429. doi:10.1016/j.devcel.2006.12.011

    Article  PubMed  CAS  Google Scholar 

  162. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, Herzlinger D, Weinmaster G, Jiang R, Gridley T (2001) Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128(4):491–502

    PubMed  CAS  Google Scholar 

  163. Krebs LT, Iwai N, Nonaka S, Welsh IC, Lan Y, Jiang R, Saijoh Y, O’Brien TP, Hamada H, Gridley T (2003) Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev 17(10):1207–1212. doi:10.1101/gad.1084703

    Article  PubMed  CAS  Google Scholar 

  164. Krebs LT, Xue Y, Norton CR, Sundberg JP, Beatus P, Lendahl U, Joutel A, Gridley T (2003) Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 37(3):139–143. doi:10.1002/gene.10241

    Article  PubMed  CAS  Google Scholar 

  165. Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111(14):1826–1832. doi:10.1161/01.cir.0000160870.93058.dd

    Article  PubMed  CAS  Google Scholar 

  166. Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, Gendron-Maguire M, Rand EB, Weinmaster G, Gridley T (1999) Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8(5):723–730

    Article  PubMed  CAS  Google Scholar 

  167. Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T (1998) Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 12(7):1046–1057

    Article  PubMed  CAS  Google Scholar 

  168. Donovan J, Kordylewska A, Jan YN, Utset MF (2002) Tetralogy of Fallot and other congenital heart defects in Hey2 mutant mice. Curr Biol 12(18):1605–1610

    Article  PubMed  CAS  Google Scholar 

  169. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18(8):901–911. doi:10.1101/gad.291004

    Article  PubMed  CAS  Google Scholar 

  170. Fischer A, Steidl C, Wagner TU, Lang E, Jakob PM, Friedl P, Knobeloch KP, Gessler M (2007) Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res 100(6):856–863. doi:10.1161/01.RES.0000260913.95642.3b

    Article  PubMed  CAS  Google Scholar 

  171. Acharya A, Hans CP, Koenig SN, Nichols HA, Galindo CL, Garner HR, Merrill WH, Hinton RB, Garg V (2011) Inhibitory role of Notch1 in calcific aortic valve disease. PLoS ONE 6(11):e27743. doi:10.1371/journal.pone.0027743

    Article  PubMed  CAS  Google Scholar 

  172. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437(7056):270–274. doi:10.1038/nature03940

    Article  PubMed  CAS  Google Scholar 

  173. Nigam V, Srivastava D (2009) Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol 47(6):828–834. doi:10.1016/j.yjmcc.2009.08.008

    Article  PubMed  CAS  Google Scholar 

  174. Nus M, MacGrogan D, Martinez-Poveda B, Benito Y, Casanova JC, Fernandez-Aviles F, Bermejo J, de la Pompa JL (2011) Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL. Arterioscler Thromb Vasc Biol 31(7):1580–1588. doi:10.1161/atvbaha.111.227561

    Article  PubMed  CAS  Google Scholar 

  175. Nakajima Y, Yamagishi T, Hokari S, Nakamura H (2000) Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP). Anat Rec 258(2):119–127

    Article  PubMed  CAS  Google Scholar 

  176. Shirai M, Imanaka-Yoshida K, Schneider MD, Schwartz RJ, Morisaki T (2009) T-box 2, a mediator of Bmp-Smad signaling, induced hyaluronan synthase 2 and Tgfbeta2 expression and endocardial cushion formation. Proc Natl Acad Sci USA 106(44):18604–18609. doi:10.1073/pnas.0900635106

    Article  PubMed  CAS  Google Scholar 

  177. Chang AC, Fu Y, Garside VC, Niessen K, Chang L, Fuller M, Setiadi A, Smrz J, Kyle A, Minchinton A, Marra M, Hoodless PA, Karsan A (2011) Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell 21(2):288–300. doi:10.1016/j.devcel.2011.06.022

    Article  PubMed  CAS  Google Scholar 

  178. Kirkbride KC, Townsend TA, Bruinsma MW, Barnett JV, Blobe GC (2008) Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor. J Biol Chem 283(12):7628–7637. doi:10.1074/jbc.M704883200

    Article  PubMed  CAS  Google Scholar 

  179. Townsend TA, Robinson JY, Deig CR, Hill CR, Misfeldt A, Blobe GC, Barnett JV (2011) BMP-2 and TGFbeta2 shared pathways regulate endocardial cell transformation. Cells Tissues Organs 194(1):1–12. doi:10.1159/000322035

    Article  PubMed  CAS  Google Scholar 

  180. Bharathy S, Xie W, Yingling JM, Reiss M (2008) Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res 68(6):1656–1666. doi:10.1158/0008-5472.can-07-5089

    Article  PubMed  CAS  Google Scholar 

  181. Daly AC, Randall RA, Hill CS (2008) Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol Cell Biol 28(22):6889–6902. doi:10.1128/mcb.01192-08

    Article  PubMed  CAS  Google Scholar 

  182. Candia AF, Watabe T, Hawley SH, Onichtchouk D, Zhang Y, Derynck R, Niehrs C, Cho KW (1997) Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. Development 124(22):4467–4480

    PubMed  CAS  Google Scholar 

  183. Kluppel M, Wrana JL (2005) Turning it up a Notch: cross-talk between TGF beta and Notch signaling. BioEssays 27(2):115–118. doi:10.1002/bies.20187

    Article  PubMed  CAS  Google Scholar 

  184. Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3(3):155–166. doi:10.1038/nrm757

    Article  PubMed  CAS  Google Scholar 

  185. Romano LA, Runyan RB (2000) Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. Dev Biol 223(1):91–102. doi:10.1006/dbio.2000.9750

    Article  PubMed  CAS  Google Scholar 

  186. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2(2):76–83. doi:10.1038/35000025

    Article  PubMed  CAS  Google Scholar 

  187. Carver EA, Jiang R, Lan Y, Oram KF, Gridley T (2001) The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 21(23):8184–8188. doi:10.1128/mcb.21.23.8184-8188.2001

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

AK and PAH are Senior Scholars of the Michael Smith Foundation for Health Research and are supported by the Heart and Stroke Foundation of Canada. VG is funded by a scholarship from the University of British Columbia. A special thanks to Rebecca Cullum for all her advice and help with editing this review.

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Authors and Affiliations

  1. Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

    Victoria C. Garside & Pamela A. Hoodless

  2. Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

    Alex C. Chang & Aly Karsan

  3. Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada

    Victoria C. Garside & Pamela A. Hoodless

  4. Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada

    Pamela A. Hoodless

  5. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada

    Aly Karsan

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  1. Victoria C. Garside
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  2. Alex C. Chang
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  3. Aly Karsan
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  4. Pamela A. Hoodless
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Correspondence to Aly Karsan or Pamela A. Hoodless.

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Garside, V.C., Chang, A.C., Karsan, A. et al. Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development. Cell. Mol. Life Sci. 70, 2899–2917 (2013). https://doi.org/10.1007/s00018-012-1197-9

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  • DOI: https://doi.org/10.1007/s00018-012-1197-9

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