Overexpression of matrix metalloproteinases leads to lethality in transgenic Xenopus laevis: Implications for tissue-dependent functions of matrix metalloproteinases during late embryonic development

The extracellular matrix (ECM) functions as the structural support of cells and as a medium for cell-cell interactions. It is understood to play criti cal roles in development. ECM remodeling is mediated largely through the ac tion of matrix metalloproteinases (MMPs), a family of Zn2+-dependent protea ses capable of degrading various proteinaceous components of the ECM, MMPs are expressed in many developmental and pathologic processes. However, few studies have been carried out to investigate the function of MMPs during em bryogenesis and postembryonic organogenesis. By using Xenopus development a s a model system, we have previously shown that several MMP genes are expre ssed from neurulation to the completion of embryogenesis in distinct tissue s/organs, suggesting that ECM remodeling during mid- to late embryogenesis occurs in an organ-specific manner. By using the recently developed transge nic technology for Xenopus laevis, we overexpressed Xenopus MMPs stromelysi n-3 (ST3) and collagenase-4 (Col4) under the control of a ubiquitous promot er and observed that embryos with overexpressed ST3 or Col4, but not the co ntrol green fluorescent protein (GFP), died in a dose-dependent manner duri ng late embryogenesis, The specificity of this embryonic lethal phenotype w as confirmed by the failure of a catalytically inactive mutant of ST3 to af fect development, Finally, overexpression of a mammalian membrane type-MMP also led to late embryonic lethality in Xenopus embryos, suggesting that me mbrane type-MMPs have functions in vivo for ECM remodeling, in addition to being activators of other pro-MMPs. These data together with the developmen tal expression of several MMPs during Xenopus development, suggest that MMP s play important roles during mid- to late embryogenesis and that proper re gulation of MMP genes is critical for tissue morphogenesis and organogenesi s. (C) 2001 Wiley-Liss, Inc.