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PMID: 19161227 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development.

Developmental dynamics : an official publication of the American Association of Anatomists ·Vol. 238 ·No. 2 ·2009-02-00 ·Pages 431-42

Azhar M, Runyan RB, Gard C, Sanford LP, Miller ML, Andringa A, Pawlowski S, Rajan S, Doetschman T

Abstract

The ligand specificity of transforming growth factor beta (TGFbeta) in vivo in mouse cardiac cushion epithelial-to-mesenchymal transition (EMT) is poorly understood. To elucidate the function of TGFbeta in cushion EMT, we analyzed Tgfb1(-/-), Tgfb2(-/-), and Tgfb3(-/-) mice between embryonic day (E) 9.5 and E14.5 using both in vitro and in vivo approaches. Atrioventricular (AV) canal collagen gel assays at E9.5 indicated normal EMT in both Tgfb1(-/-) and Tgfb3(-/-) mice. However, analysis of Tgfb2(-/-) AV explants at E9.5 and E10.5 indicated that EMT, but not cushion cell proliferation, was initially delayed but later remained persistent. This was concordant with the observation that Tgfb2(-/-) embryos, and not Tgfb1(-/-) or Tgfb3(-/-) embryos, develop enlarged cushions at E14.5 with elevated levels of well-validated indicators of EMT. Collectively, these data indicate that TGFbeta2, and not TGFbeta1 or TGFbeta3, mediates cardiac cushion EMT by promoting both the initiation and cessation of EMT.

MeSH Terms
Animals Cell Differentiation/physiology Cell Proliferation Endothelial Cells/cytology,metabolism Epithelial Cells/cytology,physiology Heart/embryology,physiology Ligands Mesoderm/cytology,embryology,metabolism Mice Mice, Knockout Transforming Growth Factor beta/genetics,physiology Transforming Growth Factor beta1/genetics,physiology Transforming Growth Factor beta2/genetics,physiology Transforming Growth Factor beta3/genetics,physiology
Chemicals
Ligands Transforming Growth Factor beta Transforming Growth Factor beta1 Transforming Growth Factor beta2 Transforming Growth Factor beta3
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Azhar Mohamad
BIO5 Institute, University of Arizona, Tucson, Arizona, USA. azharm@email.arizona.edu
Runyan Raymond B
Gard Connie
Sanford L Philip
Miller Marian L
Andringa Anastasia
Pawlowski Sharon
Rajan Sudarsan
Doetschman Thomas
References (55)
55 references, click to expand
  1. Bone morphogenetic protein-2 acts synergistically with transforming growth factor-beta3 during endothelial-mesenchymal transformation in the developing chick heart.
    J Cell Physiol. 1999 Jul;180(1):35-45 PMID: 10362015
  2. Structural development of endocardial cushions.
    Am J Anat. 1977 Jan;148(1):85-119 PMID: 842477
  3. Cell biology of cardiac cushion development.
    Int Rev Cytol. 2005;243:287-335 PMID: 15797462
  4. Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility.
    Cancer Res. 2005 Oct 1;65(19):8655-61 PMID: 16204033
  5. Self-antigen recognition by TGF beta1-deficient T cells causes their activation and systemic inflammation.
    Lab Invest. 2006 Oct;86(10):1008-19 PMID: 16865088
  6. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148.
    J Cell Biol. 2003 May 26;161(4):793-804 PMID: 12771128
  7. Sturctural analysis of endocardial cytodifferentiation.
    Dev Biol. 1975 Jan;42(1):160-80 PMID: 1112439
  8. Myocardial regulation of transforming growth factor-beta expression by outflow tract endothelium in the early embryonic chick heart.
    Dev Biol. 1994 Oct;165(2):615-26 PMID: 7958426
  9. Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-beta2.
    Circ Res. 2006 Oct 13;99(8):861-9 PMID: 16973908
  10. TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart.
    Dev Biol. 1999 Apr 15;208(2):530-45 PMID: 10191064
  11. Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor.
    J Biol Chem. 2008 Mar 21;283(12):7628-37 PMID: 18184661
  12. Congenital polyvalvular disease: a review.
    Pediatr Cardiol. 2001 Mar-Apr;22(2):93-101 PMID: 11178660
  13. RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development.
    Development. 1993 Feb;117(2):625-39 PMID: 7687212
  14. Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning.
    Development. 2005 Dec;132(24):5601-11 PMID: 16314491
  15. 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. 2007 Jun 12;115(23):3015-38 PMID: 17519398
  16. Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis.
    Dev Biol. 2002 Aug 1;248(1):170-81 PMID: 12142029
  17. Early events in valvulogenesis: a signaling perspective.
    Birth Defects Res C Embryo Today. 2003 Feb;69(1):58-72 PMID: 12768658
  18. The logic of TGFbeta signaling.
    FEBS Lett. 2006 May 22;580(12):2811-20 PMID: 16678165
  19. Valvulogenesis: the moving target.
    Philos Trans R Soc Lond B Biol Sci. 2007 Aug 29;362(1484):1489-503 PMID: 17569640
  20. Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart.
    Development. 1998 Nov;125(22):4359-67 PMID: 9778496
  21. 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. 2003 Jul;227(3):431-44 PMID: 12815630
  22. Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus.
    Circ Res. 2005 Aug 5;97(3):219-26 PMID: 16037571
  23. Opposing actions of Notch1 and VEGF in post-natal cardiac valve endothelial cells.
    Biochem Biophys Res Commun. 2008 Sep 26;374(3):512-6 PMID: 18647596
  24. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.
    Nature. 1992 Oct 22;359(6397):693-9 PMID: 1436033
  25. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.
    Genes Dev. 2004 Jan 1;18(1):99-115 PMID: 14701881
  26. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart.
    Science. 1999 Mar 26;283(5410):2080-2 PMID: 10092230
  27. Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation.
    Dev Biol. 2007 Apr 1;304(1):420-32 PMID: 17250821
  28. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated.
    Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12215-9 PMID: 8618872
  29. Essential role of endothelial Smad4 in vascular remodeling and integrity.
    Mol Cell Biol. 2007 Nov;27(21):7683-92 PMID: 17724086
  30. Signaling via the Tgf-beta type I receptor Alk5 in heart development.
    Dev Biol. 2008 Oct 1;322(1):208-18 PMID: 18718461
  31. Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.
    J Clin Invest. 2000 Aug;106(3):349-60 PMID: 10930438
  32. Cell death and differentiation in the development of the endocardial cushion of the embryonic heart.
    Microsc Res Tech. 2002 Sep 1;58(5):395-403 PMID: 12226809
  33. Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor beta.
    Dev Biol. 1989 Aug;134(2):392-401 PMID: 2744239
  34. Multiple transforming growth factor-beta isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart.
    Cells Tissues Organs. 2007;185(1-3):146-56 PMID: 17587820
  35. Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo.
    Development. 1991 Jan;111(1):131-43 PMID: 1707784
  36. The epidemiology of valvular heart diseases: the problem is growing.
    Adv Cardiol. 2004;41:9-15 PMID: 15285213
  37. Bmp2 instructs cardiac progenitors to form the heart-valve-inducing field.
    Dev Biol. 2006 Jul 15;295(2):580-8 PMID: 16730346
  38. Complexity in interpretation of embryonic epithelial-mesenchymal transition in response to transforming growth factor-beta signaling.
    Cells Tissues Organs. 2007;185(1-3):131-45 PMID: 17587819
  39. Heart valve development: endothelial cell signaling and differentiation.
    Circ Res. 2004 Sep 3;95(5):459-70 PMID: 15345668
  40. Tgfbeta signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development.
    Development. 2006 Nov;133(22):4585-93 PMID: 17050629
  41. Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart.
    Dev Biol. 2005 Oct 1;286(1):299-310 PMID: 16140292
  42. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes.
    Development. 1997 Jul;124(13):2659-70 PMID: 9217007
  43. Microarray analysis of gene expression during early stages of mild and severe cardiac hypertrophy.
    Physiol Genomics. 2006 Nov 27;27(3):309-17 PMID: 16882888
  44. A new mathematical model for relative quantification in real-time RT-PCR.
    Nucleic Acids Res. 2001 May 1;29(9):e45 PMID: 11328886
  45. VE-cadherin is a critical endothelial regulator of TGF-beta signalling.
    EMBO J. 2008 Apr 9;27(7):993-1004 PMID: 18337748
  46. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction.
    Nat Genet. 1995 Dec;11(4):415-21 PMID: 7493022
  47. Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2.
    J Cell Biol. 2003 Feb 17;160(4):605-15 PMID: 12591918
  48. Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes.
    J Biol Chem. 2007 Sep 7;282(36):26517-27 PMID: 17597066
  49. Nf1 has an essential role in endothelial cells.
    Nat Genet. 2003 Jan;33(1):75-9 PMID: 12469121
  50. Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype.
    Cancer Res. 2008 Mar 15;68(6):1656-66 PMID: 18339844
  51. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770-4 PMID: 8421714
  52. 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 Jun 5;103(22):2745-52 PMID: 11390347
  53. Transforming growth factor-beta 3 is required for secondary palate fusion.
    Nat Genet. 1995 Dec;11(4):409-14 PMID: 7493021
  54. Sense and antisense TGF beta 3 mRNA levels correlate with cardiac valve induction.
    Dev Dyn. 1992 Apr;193(4):340-5 PMID: 1511174
  55. Transforming growth factor beta in cardiovascular development and function.
    Cytokine Growth Factor Rev. 2003 Oct;14(5):391-407 PMID: 12948523
Article Info
Journal
Developmental dynamics : an official publication of the American Association of Anatomists
Abbr.
Dev Dyn
ISSN
1058-8388
DOI
10.1002/dvdy.21854
Email
azharm@email.arizona.edu
Published
2009-02-00
Pages
431-42
Language
English
Region
United States
NLM ID
9201927
PMCID
PMC2805850
Subset
IM
Grants
NHLBI NIH HHS · R01 HL075633-01A1 · United States
NICHD NIH HHS · R01 HD026471-11A1 · United States
NHLBI NIH HHS · R01 HL070174-04 · United States
NIEHS NIH HHS · P30 ES006694 · United States
NHLBI NIH HHS · R01 HL092508 · United States
NHLBI NIH HHS · R01 HL092508-01A1 · United States
NICHD NIH HHS · R01 HD26471 · United States
NICHD NIH HHS · R01 HD026471 · United States
NICHD NIH HHS · R01 HD026471-13 · United States
NHLBI NIH HHS · R01 HL075633 · United States
NHLBI NIH HHS · R01 HL082851 · United States
NICHD NIH HHS · R01 HD026471-14 · United States
NICHD NIH HHS · R01 HD026471-12 · United States
NICHD NIH HHS · R01 HD82851 · United States
NICHD NIH HHS · R01 HD026471-15 · United States
NHLBI NIH HHS · R01 HL070174 · United States
External Links
PubMed source DOI: 10.1002/dvdy.21854 PMC Full Text View journal details
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