Establishment of an MT4-MMP-deficient mouse strain representing an efficient tracking system for MT4-MMP/MMP-17 expression in vivo using beta-galactosidase.
The biological functions of membrane-type 4 matrix metalloproteinase (MT4-MMP/MMP-17) are poorly understood because of the lack of a sensitive system for tracking its expression in vivo. We established a mutant mouse strain (Mt4-mmp(-/-)) in which Mt4-mmp was replaced with a reporter gene encoding beta-galactosidase (LacZ). Mt4-mmp(-/-) mice had normal gestations, and no apparent defects in growth, life span and fertility. Using LacZ as a marker, we were able to monitor the expression and promoter activity of Mt4-mmp for the first time in vivo. The tissue distribution of Mt4-mmp mRNA correlated with LacZ expression, and we showed that Mt4-mmp is expressed primarily in cerebrum, lung, spleen, intestine and uterus. We identified LacZ-positive neurons in the cerebrum, smooth muscle cells in the intestine and uterus, and macrophages located in the lung alveolar or intraperitoneal space. Contrary to the reported role of MT4-MMP as a tumor necrosis factor-alpha (TNF-alpha) sheddase, the lipopolysaccharide (LPS)-induced release of TNF-alpha from Mt4-mmp(-/-)macrophages was similar to that in wild-type cells, and expression of Mt4-mmp mRNA was repressed following LPS stimulation. Thus, we have established a mutant mouse strain for analyzing the physiological functions of MT4-MMP, which also serves as a sensitive system for monitoring and tracking the expression of MT4-MMP in vivo.
Rikimaru
Akiko
A
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
Komori
Kiyoshi
K
Sakamoto
Takeharu
T
Ichise
Hirotake
H
Yoshida
Nobuaki
N
Yana
Ikuo
I
Seiki
Motoharu
M
D000818:Animals; D054022:Cerebrum / Q000378:metabolism; D017930:Genes, Reporter; D007763:Lac Operon; D053515:Matrix Metalloproteinase 17 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001616:beta-Galactosidase / Q000032:analysis* / Q000235:genetics