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PMID: 10811845 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development.

The Journal of clinical investigation ·Vol. 105 ·No. 10 ·2000-05-00 ·Pages 1373-82

Yanagisawa H, Hammer RE, Richardson JA, Emoto N, Williams SC, Takeda Si, Clouthier DE, Yanagisawa M

Abstract

Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest-derived tissues, including branchial arch-derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1-null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1(-/-); ECE-2(-/-) double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1(-/-); ECE-2(-/-) embryos at E12.5 do not differ appreciably from those of ECE-1(-/-) embryos. The significant residual ET-1/ET-2 in the ECE-1(-/-); ECE-2(-/-) embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.

MeSH Terms
Animals Aspartic Acid Endopeptidases/genetics,physiology Base Sequence DNA Primers/genetics Endothelin-1/metabolism Endothelin-2/metabolism Endothelin-Converting Enzymes Female Fetal Heart/embryology,enzymology Gene Expression Regulation, Developmental Gene Expression Regulation, Enzymologic Heart Defects, Congenital/enzymology,genetics,pathology In Situ Hybridization In Vitro Techniques Male Metalloendopeptidases/genetics,physiology Mice Mice, Inbred C57BL Mice, Knockout Pregnancy RNA, Messenger/genetics,metabolism Tissue Distribution
Chemicals
DNA Primers Endothelin-1 Endothelin-2 RNA, Messenger Aspartic Acid Endopeptidases Metalloendopeptidases Ece1 protein, mouse Ece2 protein, mouse Endothelin-Converting Enzymes
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Yanagisawa H
Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75390-9050, USA.
Hammer R E
Richardson J A
Emoto N
Williams S C
Takeda S i
Clouthier D E
Yanagisawa M
References (32)
32 references, click to expand
  1. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5.
    Nature. 1991 Apr 11;350(6318):473-9 PMID: 1673020
  2. Molecular regulation of atrioventricular valvuloseptal morphogenesis.
    Circ Res. 1995 Jul;77(1):1-6 PMID: 7788867
  3. Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4.
    Nature. 1996 Apr 25;380(6576):711-4 PMID: 8614465
  4. 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
  5. Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression.
    J Immunol. 1993 May 1;150(9):4168-78 PMID: 8473755
  6. Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1.
    J Clin Invest. 1995 Jul;96(1):293-300 PMID: 7615798
  7. Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development.
    Nat Genet. 1996 Oct;14(2):210-3 PMID: 8841198
  8. The Splotch (Sp1H) and Splotch-delayed (Spd) alleles: differential phenotypic effects on neural crest and limb musculature.
    Anat Embryol (Berl). 1993 Apr;187(4):371-7 PMID: 8512089
  9. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.
    Genes Dev. 1994 May 1;8(9):1019-29 PMID: 7926784
  10. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene.
    Development. 1998 Mar;125(5):825-36 PMID: 9449665
  11. Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development.
    Dev Biol. 1998 Jun 1;198(1):32-44 PMID: 9640330
  12. Neural crest and cardiovascular patterning.
    Circ Res. 1995 Aug;77(2):211-5 PMID: 7614707
  13. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.
    Cell. 1994 Dec 30;79(7):1267-76 PMID: 8001159
  14. Cell origins and tissue boundaries during outflow tract development.
    Trends Cardiovasc Med. 1995 Mar-Apr;5(2):69-75 PMID: 21232240
  15. Requirement for neuregulin receptor erbB2 in neural and cardiac development.
    Nature. 1995 Nov 23;378(6555):394-8 PMID: 7477377
  16. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.
    Nature. 1988 Mar 31;332(6163):411-5 PMID: 2451132
  17. ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1.
    Cell. 1994 Aug 12;78(3):473-85 PMID: 8062389
  18. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor.
    Nature. 1995 Nov 23;378(6555):390-4 PMID: 7477376
  19. RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice.
    J Clin Invest. 1996 Sep 15;98(6):1332-43 PMID: 8823298
  20. Organization of the gene encoding the human endothelin-converting enzyme (ECE-1).
    J Biol Chem. 1995 Dec 15;270(50):29794-8 PMID: 8530372
  21. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1.
    Nature. 1994 Apr 21;368(6473):703-10 PMID: 8152482
  22. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.
    Cell. 1994 Dec 30;79(7):1277-85 PMID: 8001160
  23. Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum.
    J Biol Chem. 1995 Jun 23;270(25):15262-8 PMID: 7797512
  24. Cloning and expression of a cDNA encoding an endothelin receptor.
    Nature. 1990 Dec 20-27;348(6303):730-2 PMID: 2175396
  25. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.
    Nature. 1990 Dec 20-27;348(6303):732-5 PMID: 2175397
  26. Origins and patterning of avian outflow tract endocardium.
    Development. 1991 Apr;111(4):867-76 PMID: 1879358
  27. Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice.
    J Clin Invest. 1998 Jul 1;102(1):22-33 PMID: 9649553
  28. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.
    Proc Natl Acad Sci U S A. 1989 Apr;86(8):2863-7 PMID: 2649896
  29. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice.
    Development. 1998 Mar;125(5):813-24 PMID: 9449664
  30. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants.
    Development. 1994 Oct;120(10):2749-71 PMID: 7607068
  31. A sandwich-type enzyme immunoassay to detect immunoreactive big-endothelin-1 in plasma.
    J Immunol Methods. 1990 Mar 9;127(2):165-70 PMID: 2179411
  32. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse.
    Genes Dev. 1997 Jul 15;11(14):1812-26 PMID: 9242489
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI7447
Published
2000-05-00
Pages
1373-82
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC315458
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI7447 PMC Full Text View journal details
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