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Molecular and Cellular Biology, March 2002, p. 1537-1544, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1537-1544.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mice Lacking the Metalloprotease-Disintegrin MDC9 (ADAM9) Have No Evident Major Abnormalities during Development or Adult Life

Gisela Weskamp,1 Hui Cai,1 Thomas A. Brodie,2 Shigeki Higashyama,3 Katia Manova,4 Thomas Ludwig,5 and Carl P. Blobel1*

Cellular Biochemistry and Biophysics Program,1 Molecular Cytology Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,4 Department of Pathology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709,2 Department of Biochemistry, School of Allied Health Science, Osaka University Faculty of Medicine, Osaka 565-0897, Japan,3 Department of Anatomy & Cell Biology, Columbia University, New York, New York 100325

Received 3 October 2001/ Accepted 26 November 2001

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 ß- and {gamma}-secretase cleavage product (Aß) 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.

* Corresponding author. Mailing address: Cellular Biochemistry and Biophysics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Box 368, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2915. Fax: (212) 717-3047. E-mail: c-blobel{at}ski.mskcc.org.

Molecular and Cellular Biology, March 2002, p. 1537-1544, Vol. 22, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.5.1537-1544.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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