Abstract
The matrix metalloproteinase (MMP) family (∼25 members in mammals) has been implicated in extracellular matrix remodeling associated with embryonic development, cancer formation and progression, and various other physiological and pathological events. Inactivating mutations in individual matrix metalloproteinase genes in mice described so far, however, are nonlethal at least up to the first few weeks after birth, suggesting functional redundancy among MMP family members. Here, we report that mice lacking two MMPs, MMP-2 (nonmembrane type) and MT1-MMP (membrane type), die immediately after birth with respiratory failure, abnormal blood vessels, and immature muscle fibers reminiscent of central core disease. In the absence of MMP-2 and MT1-MMP, myoblast fusion in vitro is also significantly retarded. These findings suggest functional overlap in mice between the two MMPs with distinct molecular natures.
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Acknowledgements
We thank Emi Nishimoto, Takashi Kawai, and Mari Kojima for technical assistance; Yukio Imamura, Yoko Morioka, Michiko Echizenya, Shu Liang Shi, and Kei-ichi Inoue for help in animal maintenance; and Aki Miyazaki and Keiko Shimizu for secretarial assistance. This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan.
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Oh, J., Takahashi, R., Adachi, E. et al. Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice. Oncogene 23, 5041–5048 (2004). https://doi.org/10.1038/sj.onc.1207688
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DOI: https://doi.org/10.1038/sj.onc.1207688
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