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Molecular and Cellular Biology, February 2003, p. 1221-1230, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1221-1230.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Meprin ß Gene in Mice Leads to Underrepresentation of Knockout Mice and Changes in Renal Gene Expression Profiles

Lourdes P. Norman,¹ Weiping Jiang,^1, Xiaoli Han,¹ Thomas L. Saunders,² and Judith S. Bond^1*

Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Hershey, Pennsylvania 17033-0850,¹ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109²

Received 29 July 2002/ Returned for modification 10 September 2002/ Accepted 7 November 2002

Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes and in leukocytes and certain cancer cells. Mature meprins are oligomers of evolutionarily related, separately encoded and/or ß subunits. Homooligomers of meprin are secreted; oligomers containing meprin ß are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin ß is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin ß null mice were generated by targeted disruption of the meprin ß gene on mouse chromosome 18q12. Analyses of meprin ß knockout mice indicated that (i) 50% fewer null mice are born than the Mendelian distribution predicts, (ii) null mice that survive develop normally and are viable and fertile, (iii) meprin ß knockout mice lack membrane-associated meprin in kidney and intestine, and (iv) null mice have changes in renal gene expression profiles compared to wild-type mice as assessed by microarray analyses. Thus, disruption of the meprin ß allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin in kidney and intestine.

Present address: R & D Systems Inc., Minneapolis, MN 55413.

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