title: Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse.
abstract: Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the COOH-terminal amidation of peptide hormones. We previously had found high expression of PAM in several regions of the developing rodent. To determine the function of PAM during mouse embryogenesis, we produced a null mutant of the PAM gene. Homozygous mutants die in utero between e14.5 and e15.5 with severe edema that is likely due to cardiovascular deficits. These defects include thinning of the aorta and carotid arteries and are very similar to those of the recently characterized adrenomedullin (AM) gene KO despite the presence of elevated immunoreactive AM in PAM KO embryos. No peptide amidation activity was detected in PAM mutant embryos, and there was no moderation of the AM-like phenotype that could be expected if any alternative peptide amidation mechanism exists in the mouse. Despite the proposed contribution of amidated peptides to neuronal cell proliferation, no alteration in neuroblast proliferation was observed in homozygous mutant embryos prior to lethality. Mice heterozygous for the mutant PAM allele develop normally and express wildtype levels of several amidated peptides despite having one half the wildtype levels of PAM activity and PAM protein. Nonetheless, both an increase in adiposity and a mild glucose intolerance developed in aged (>10 months) heterozygous mice compared to littermate controls. Ablation of PAM thus demonstrates an essential function for this gene during mouse development, while alterations in PAM activity in the adult may underlie more subtle physiologic effects.
authors.affiliation: Department of Neuroscience and Cell Biology, CABM Rm 326, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
authors.forename: Traci A
authors.initials: TA
authors.lastname: Czyzyk
authors.forename: Yun
authors.initials: Y
authors.lastname: Ning
authors.forename: Ming-Sing
authors.initials: MS
authors.lastname: Hsu
authors.forename: Bonnie
authors.initials: B
authors.lastname: Peng
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology; D001921:Brain / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D004487:Edema / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000201:enzymology; D005260:Female; D005951:Glucose Tolerance Test; D006352:Heart Ventricles / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D008168:Lung / Q000002:abnormalities / Q000196:embryology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D015017:Yolk Sac / Q000002:abnormalities / Q000098:blood supply / Q000196:embryology
chemical_list: D009097:Multienzyme Complexes; D010455:Peptides; D053607:Adrenomedullin; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase