Differential Regulation of Cell Type-specific Apoptosis by Stromelysin-3

Abstract

Matrix metalloproteinases (MMPs) have been extensively studied because of their functional attributes in development and diseases. However, relatively few in vivo functional studies have been reported on the roles of MMPs in postembryonic organ development. Amphibian metamorphosis is a unique model for studying MMP function during vertebrate development because of its dependence on thyroid hormone (T3) and the ability to easily manipulate this process with exogenous T3. The MMP stromelysin-3 (ST3) is induced by T3, and its expression correlates with cell death during metamorphosis. We have previously shown that ST3 is both necessary and sufficient for larval epithelial cell death in the remodeling intestine. To investigate the roles of ST3 in other organs and especially on different cell types, we have analyzed the effect of transgenic overexpression of ST3 in the tail of premetamorphic tadpoles. We report for the first time that ST3 expression, in the absence of T3, caused significant muscle cell death in the tail of premetamorphic transgenic tadpoles. On the other hand, 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. This cell type-specific apoptotic response to ST3 in the tail suggests distinct mechanisms regulating cell death in different tissues. Furthermore, our analyses of laminin receptor, an in vivo substrate of ST3 in the intestine, suggest that laminin receptor cleavage may be an underlying mechanism for the cell type-specific effects of ST3. The extracellular matrix (ECM),3 the dynamic milieu of the cell microenvironment, plays a critical role in dictating the fate of the cell. The cross-talk between the cell and ECM and the timely catabolism of the ECM are crucial for tissue remodeling during development (1). Matrix metalloproteinases (MMPs), extrinsic proteolytic regulators of the ECM, mediate this process to a large extent. MMPs are a large family of Zn 2ϩ -dependent endopeptidases potentially capable of cleaving the extracellular as well as nonextracellular proteins (2-9). The MMP superfamily includes collagenases, gelatinases, stromelysins, and membrane-type MMPs based on substrate specificity and domain organization (2-4). MMPs have been implicated to influence a wide range of physiological and pathological processes (10 -13). The roles of MMPs appear to be very complex. For example, MMPs have been suggested to play roles in both tumor promotion and suppression (13-19). Unfortunately, relatively few functional studies have been carried out in vivo, especially in relation to the mechanisms involved during vertebrate development.Amphibian metamorphosis presents a fascinating experimental model to study MMP function during postembryonic development. A unique and salient feature of the metamorphic process is the absolute dependence on the signaling of thyroid hormone (20 -23). This makes it possible to prevent metamorphosis by simply inhibit...

Transdifferentiation of tadpole pancreatic acinar cells to duct cells mediated by Notch and stromelysin-3

“…ST3 has been implicated in the remodeling of the intestine at the climax of metamorphosis (Ishizuya-Oka et al, 2000). X laevis transgenic for ST3 controlled by a heat shock promoter enhances apoptosis of tail muscle (Mathew et al, 2009). These associations of ST3 and its dramatic TH-induced up regulation in the exocrine pancreas (Fig.…”

Tissue‐dependent induction of apoptosis by matrix metalloproteinase stromelysin‐3 during amphibian metamorphosis

“…On the other hand, during natural metamorphosis, comparable levels of apoptotic cells are detected in both the epidermis and muscles of the tail around stage 61, right before rapid reduction in tail length when ST3 mRNA levels are significantly up-regulated (Fig. 4A) (Mathew and others, 2009). By stage 63, with even higher levels of ST3 expression, the number of apoptotic cells in both tissues, especially the epidermis, increases dramatically (Fig.…”

“…By stage 63, with even higher levels of ST3 expression, the number of apoptotic cells in both tissues, especially the epidermis, increases dramatically (Fig. 4B) (Damjanovski and others, 1999; Mathew and others, 2009). Interestingly, when wild type premetamorphic tadpoles were treated with physiological levels of T3 for several days (before any significant reduction in tail length), cell death was much higher in the muscles than in the epidermis and the ST3 mRNA level induced by T3-treatment was also much lower than that at stage 63 (Mathew and others, 2009).…”

“…3) (Mathew and others, 2009). On the other hand, during natural metamorphosis, comparable levels of apoptotic cells are detected in both the epidermis and muscles of the tail around stage 61, right before rapid reduction in tail length when ST3 mRNA levels are significantly up-regulated (Fig.…”

“…4B) (Damjanovski and others, 1999; Mathew and others, 2009). Interestingly, when wild type premetamorphic tadpoles were treated with physiological levels of T3 for several days (before any significant reduction in tail length), cell death was much higher in the muscles than in the epidermis and the ST3 mRNA level induced by T3-treatment was also much lower than that at stage 63 (Mathew and others, 2009). These results suggest that very high levels of ST3 expression in the connective tissue underlying the epidermis are needed for epidermal apoptosis in the tail during metamorphosis.…”