Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice.
The matrix metalloproteinase (MMP) family (approximately 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.
Oh
Junseo
J
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Takahashi
Rei
R
Adachi
Eijiro
E
Kondo
Shunya
S
Kuratomi
Shinobu
S
Noma
Akinori
A
Alexander
David B
DB
Motoda
Hirotoshi
H
Okada
Akiko
A
Seiki
Motoharu
M
Itoh
Takeshi
T
Itohara
Shigeyoshi
S
Takahashi
Chiaki
C
Noda
Makoto
M
D000818:Animals; D001808:Blood Vessels / Q000196:embryology* / Q000473:pathology*; D005804:Genes, Lethal; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000196:embryology* / Q000473:pathology; D009154:Mutation; D032446:Myoblasts / Q000473:pathology; D009389:Neovascularization, Pathologic
C507096:Mmp14 protein, mouse; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14