Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene

Hiromi Yanagisawa, Masashi Yanagisawa, Raj P. Kapur, James A Richardson, S. Clay Williams, David E. Clouthier, Damiane De Wit, Noriaki Emoto, Robert E Hammer

Research output: Contribution to journalArticle

402 Citations (Scopus)

Abstract

Recent gene targeting studies have revealed unexpected roles for endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to endothelin-1(ET-1) in vitro. However, the importance of ECE-1 cleavage in the multiple endothelin pathways in vivo is unknown. Here we generated a targeted null mutation in the mouse ECE-1 gene. ECE-1(-/-) term embryos exhibited craniofacial and cardiac abnormalities virtually identical to the defects seen in ET-1 and endothelin A receptor (ET(A))-deficient embryos. Epidermal melanocytes as well as enteric neurons of the distal gut were also absent in ECE-1(-/-) embryos, reproducing the developmental phenotype seen in ET-3(-/-) and endothelin B receptor (ET(B))(-/-) mice. Surprisingly, large amounts of mature ET-1 peptide are found in ECE-1(-/-) embryos, indicating that non-ECE-1 protease(s) can activate ET-1 at certain sites. However, these enzymes cannot produce sufficient mature endothelin at the locations crucial for normal embryonic development. These findings reveal that ECE-1 is a bona fide activating protease for both big ET-1 and big ET-3 in vivo, and that the cell-cell communication pathways represented by the ET-1/ECE-1/ET(A) axis and the ET-3/ECE-1/ET(B) axis are each involved in the development of distinct subsets of neural crest cell lineages. Mutations in ECE-1 may cause developmental defects in humans, such as Hirschsprung disease, velocardiofacial syndrome and related neurocristopathies.

Original languageEnglish (US)
Pages (from-to)825-836
Number of pages12
JournalDevelopment
Volume125
Issue number5
StatePublished - 1998

Fingerprint

Endothelins
Endothelin-1
Genes
Embryonic Structures
Endothelin A Receptors
Neural Crest
Peptide Hydrolases
Craniofacial Abnormalities
Endothelin B Receptors
DiGeorge Syndrome
Endothelin-Converting Enzymes
Hirschsprung Disease
Mutation
Gene Targeting
Melanocytes
Cell Lineage
Enzymes
Cell Communication
Embryonic Development
Phenotype

Keywords

  • Branchial arch
  • ECE-1
  • Enteric neuron
  • Heart
  • Melanocyte
  • Mouse
  • Neural crest
  • Protease

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. / Yanagisawa, Hiromi; Yanagisawa, Masashi; Kapur, Raj P.; Richardson, James A; Williams, S. Clay; Clouthier, David E.; De Wit, Damiane; Emoto, Noriaki; Hammer, Robert E.

In: Development, Vol. 125, No. 5, 1998, p. 825-836.

Research output: Contribution to journalArticle

Yanagisawa, Hiromi ; Yanagisawa, Masashi ; Kapur, Raj P. ; Richardson, James A ; Williams, S. Clay ; Clouthier, David E. ; De Wit, Damiane ; Emoto, Noriaki ; Hammer, Robert E. / Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. In: Development. 1998 ; Vol. 125, No. 5. pp. 825-836.
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AB - Recent gene targeting studies have revealed unexpected roles for endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to endothelin-1(ET-1) in vitro. However, the importance of ECE-1 cleavage in the multiple endothelin pathways in vivo is unknown. Here we generated a targeted null mutation in the mouse ECE-1 gene. ECE-1(-/-) term embryos exhibited craniofacial and cardiac abnormalities virtually identical to the defects seen in ET-1 and endothelin A receptor (ET(A))-deficient embryos. Epidermal melanocytes as well as enteric neurons of the distal gut were also absent in ECE-1(-/-) embryos, reproducing the developmental phenotype seen in ET-3(-/-) and endothelin B receptor (ET(B))(-/-) mice. Surprisingly, large amounts of mature ET-1 peptide are found in ECE-1(-/-) embryos, indicating that non-ECE-1 protease(s) can activate ET-1 at certain sites. However, these enzymes cannot produce sufficient mature endothelin at the locations crucial for normal embryonic development. These findings reveal that ECE-1 is a bona fide activating protease for both big ET-1 and big ET-3 in vivo, and that the cell-cell communication pathways represented by the ET-1/ECE-1/ET(A) axis and the ET-3/ECE-1/ET(B) axis are each involved in the development of distinct subsets of neural crest cell lineages. Mutations in ECE-1 may cause developmental defects in humans, such as Hirschsprung disease, velocardiofacial syndrome and related neurocristopathies.

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