DISTINCT FUNCTION OF DIFFERENT MMPS AND A REQUIREMENT FOR PROPER LEVELS OF MMP ACIVITIES DURING DEVELOPMENT. We have previously shown that the MMP stromelysin-3 (ST3) is induced by TH and its expression correlated with cell death during metamorphosis. We have further demonstrated that ST3 is both necessary and sufficient for larval epithelial cell death in the remodeling intestine. On the other hand, ST3 expression, in the absence of T3, caused significant muscle cell death in the tail of premetamorphic transgenic tadpoles, while only relatively low levels of epidermal cell death were induced by precocious ST3 expression in the tail, contrasting what takes place during natural and T3-induced metamorphosis when ST3 expression is high. We have further provided evidence that these differential effects of ST3 may be mediated by its cleavage of the laminin receptor, an in vivo substrate of ST3. To investigate whether other MMPs may also regulate cell fate during metamorphosis, we have carried out transgenic studies on another metamorphosis-associated MMP, the membrane-type 1 MMP or MT1-MMP. Interestingly, overexpression of this MMP caused lethality in metamorphosis tadpoles although little effect on apoptosis has been observed. Thus, different MMPs indeed have distinct roles during metamorphosis. To inhibit MMP activities in vivo, we carried out a transgenic study where we overexpressed the tissue inhibitor of MMP (TIMP)-2, which is also induced during metamorphosis. Surprisingly, overexpression of TIMP2 also caused lethality in metamorphosis tadpoles without affecting apoptosis. On the other hand, crossing the TIMP2 and MT1-MMP transgenic animals rescued this lethal phenotype. Thus, proper balance of MMP activities is critical for metamorphosis.

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