Targeted disruption of the meprin beta gene in mice leads to underrepresentation of knockout mice and changes in renal gene expression profiles.
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 alpha and/or beta subunits. Homooligomers of meprin alpha are secreted; oligomers containing meprin beta are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin beta is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin beta null mice were generated by targeted disruption of the meprin beta gene on mouse chromosome 18q12. Analyses of meprin beta 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 beta knockout mice lack membrane-associated meprin alpha 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 beta allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin alpha in kidney and intestine.
Norman
Lourdes P
LP
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Hershey, Pennsylvania 17033-0850, USA.
Jiang
Weiping
W
Han
Xiaoli
X
Saunders
Thomas L
TL
Bond
Judith S
JS
D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D005260:Female; D005313:Fetal Death / Q000235:genetics; D020869:Gene Expression Profiling; D007422:Intestines / Q000502:physiology; D007668:Kidney / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism
D012333:RNA, Messenger; D008666:Metalloendopeptidases; C053833:meprin A; C095663:meprin B