MT1-MMP-mediated basement membrane remodeling modulates renal development.
Extracellular matrix (ECM) remodeling regulates multiple cellular functions required for normal development and tissue repair. Matrix metalloproteinases (MMPs) are key mediators of this process and membrane targeted MMPs (MT-MMPs) in particular have been shown to be important in normal development of specific organs. In this study we investigated the role of MT1-MMP in kidney development. We demonstrate that loss of MT1-MMP leads to a renal phenotype characterized by a moderate decrease in ureteric bud branching morphogenesis and a severe proliferation defect. The kidneys of MT1-MMP-null mice have increased deposition of collagen IV, laminins, perlecan, and nidogen and the phenotype is independent of the MT-1MMP target, MMP-2. Utilizing in vitro systems we demonstrated that MTI-MMP proteolytic activity is required for renal tubule cells to proliferate in three dimensional matrices and to migrate on collagen IV and laminins. Together these data suggest an important role for MT1-MMP in kidney development, which is mediated by its ability to regulate cell proliferation and migration by proteolytically cleaving kidney basement membrane components.
Riggins
Karen S
KS
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Mernaugh
Glenda
G
Su
Yan
Y
Quaranta
Vito
V
Koshikawa
Naohiko
N
Seiki
Motoharu
M
Pozzi
Ambra
A
Zent
Roy
R
D000818:Animals; D001485:Basement Membrane / Q000166:cytology / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D005109:Extracellular Matrix; D007668:Kidney / Q000166:cytology / Q000254:growth & development*; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
C507096:Mmp14 protein, mouse; D053511:Matrix Metalloproteinase 14