title: Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene.
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 (ETA)-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 (ETB)-/- 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/ETA axis and the ET-3/ECE-1/ETB 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9050, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yanagisawa
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: R P
authors.initials: RP
authors.lastname: Kapur
authors.forename: J A
authors.initials: JA
authors.lastname: Richardson
authors.forename: S C
authors.initials: SC
authors.lastname: Williams
authors.forename: D E
authors.initials: DE
authors.lastname: Clouthier
authors.forename: D
authors.initials: D
authors.lastname: de Wit
authors.forename: N
authors.initials: N
authors.lastname: Emoto
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018390:Gene Targeting; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D016232:Endothelins; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes