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PMID: 11839819 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life.

Molecular and cellular biology ·Vol. 22 ·No. 5 ·2002-03-00 ·Pages 1537-44

Weskamp G, Cai H, Brodie TA, Higashyama S, Manova K, Ludwig T, Blobel CP

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.

MeSH Terms
ADAM Proteins Amyloid Precursor Protein Secretases Amyloid beta-Protein Precursor/metabolism Animals Aspartic Acid Endopeptidases Disintegrins/deficiency,genetics,isolation & purification Embryo, Mammalian/enzymology Endopeptidases/metabolism Epidermal Growth Factor/metabolism Heparin-binding EGF-like Growth Factor Hippocampus/cytology,metabolism Homozygote Intercellular Signaling Peptides and Proteins Membrane Proteins Metalloendopeptidases/deficiency,genetics,isolation & purification Mice Mice, Inbred C57BL Mice, Mutant Strains Neurons/metabolism Protein Processing, Post-Translational Tissue Distribution
Chemicals
Amyloid beta-Protein Precursor Disintegrins Hbegf protein, mouse Heparin-binding EGF-like Growth Factor Intercellular Signaling Peptides and Proteins Membrane Proteins Epidermal Growth Factor Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases Bace1 protein, mouse ADAM Proteins Adam9 protein, mouse Metalloendopeptidases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Weskamp Gisela
Cellular Biochemistry and Biophysics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cai Hui
Brodie Thomas A
Higashyama Shigeki
Manova Katia
Ludwig Thomas
Blobel Carl P
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.5.1537-1544.2002
Published
2002-03-00
Pages
1537-44
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC134708
Subset
IM
Grants
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · P30-CA-08748 · United States
NIGMS NIH HHS · R01 GM58668 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.5.1537-1544.2002 PMC Full Text View journal details
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