title: Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life.
abstract: MDC9 (ADAM9/meltrin gamma) is a widely expressed and catalytically active metalloprotease-disintegrin protein that has been implicated in the ectodomain cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and as an alpha secretase for the amyloid precursor protein. In this study, we evaluated the expression of MDC9 during development and generated mice lacking MDC9 (mdc9(-/-) mice) to learn more about the function of this protein during development and in adults. During mouse development, MDC9 mRNA is ubiquitously expressed, with particularly high expression levels in the developing mesenchyme, heart and brain. Despite the ubiquitous expression of MDC9, mdc9(-/-) mice appear to develop normally, are viable and fertile, and do not have any major pathological phenotypes compared to wild-type mice. Constitutive and stimulated ectodomain shedding of HB-EGF is comparable in embryonic fibroblasts isolated from mdc9(-/-) and wild-type mice, arguing against an essential role of MDC9 in HB-EGF shedding in these cells. Furthermore, there were no differences in the production of the APP alpha and gamma secretase cleavage product (p3) and of beta- and gamma-secretase cleavage product (A beta) in cultured hippocampal neurons from mdc9(-/-) or wild-type mice, arguing against an essential major role of MDC9 as an alpha-secretase in mice. Further studies, including functional challenges and an evaluation of potential compensation by, or redundancy with, other members of the ADAM family or perhaps even with other molecules will be necessary to uncover physiologically relevant functions for MDC9 in mice.
authors.affiliation: Cellular Biochemistry and Biophysics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Gisela
authors.initials: G
authors.lastname: Weskamp
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brodie
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashyama
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D051722:ADAM Proteins; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019483:Disintegrins / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D004622:Embryo, Mammalian / Q000201:enzymology; D010450:Endopeptidases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006720:Homozygote; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D014018:Tissue Distribution
chemical_list: D016564:Amyloid beta-Protein Precursor; D019483:Disintegrins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D004815:Epidermal Growth Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; C498316:Adam9 protein, mouse; D008666:Metalloendopeptidases