TRANSCRIPTIONAL ACTIVATION OF THE MATRIX METALLOPROTEINASE GENE STROMELYSIN-3 COINCIDES WITH THYROID HORMONE-INDUCED CELL-DEATH DURING FROGMETAMORPHOSIS

A full-length cDNA was isolated for a thyroid hormone response gene in the metamorphosing frog intestine and shown by sequence analysis to b e the frog homolog of the mammalian extracellular matrix metalloprotei nase stromelysin-3 (ST3). Northern hybridization indicated that ST3 ge ne expression is differentially activated in tadpole tissues during me tamorphosis. In the small intestine, in situ hybridization localized h igh levels of ST3 mRNA to fibroblast-like cells during thyroid hormone -induced metamorphosis. ST3 mRNA was undetectable in the intestine pri or to metamorphosis, while high levels were present at the metamorphic climax. At this time, primary intestinal epithelial cells are known t o undergo cell death and replacement by secondary epithelial cells, ar guing that ST3 is involved in the modification of the extracellular ma trix during apoptosis. ST3 mRNA was also expressed at high levels duri ng tadpole tail resorption, but not in premetamorphic tail or developi ng hindlimb, further supporting a role for ST3 when tissue remodeling is accompanied by large-scale cell death. Premetamorphic tadpoles trea ted with thyroid hormone showed a similar but compressed time course o f ST3 gene regulation, suggesting that thyroid hormone controls ST3 ge ne expression during metamorphosis. In contrast, during embryogenesis, ST3 was expressed before endogenous thyroid hormone is detectable, in dicating that ST3 can also be regulated independently of thyroid hormo ne. These findings implicate that ST3 participates in the modification of the extracellular matrix during metamorphic apoptosis, but Norther n analyses using heterologous probes raise the possibility that additi onal matrix metalloproteinases may also be involved. (C) 1995 Academic Press, Inc.