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Intestinal metamorphosis in anurans is an excellent model system for studying post-embryonic tissue remodeling and organ development in vertebrates. This process involves degeneration of the larval or tadpole form of its primary functional tissue, the simple tubular epithelium through apoptosis or programmed cell death. Concurrently, adult epithelial stem cells, whose origin remains to be determined, proliferate and differentiate to form a multiply folded, complex adult epithelium. The connective tissue and muscles also develop extensively during this period. Like all other changes during amphibian metamorphosis, intestinal remodeling is controlled by thyroid hormone (TH). Isolation and characterization of genes that are regulated by TH has implicated the involvement of matrix metalloproteinases (MMPs) in the remodeling of the extracellular matrix (ECM) during intestinal metamorphosis. Here we will review some studies, almost exclusively in Xenopus laevis, that support a role of MMPs, particularly stromelysin 3, and ECM remodeling in regulating cell fate and tissue morphogenesis.
Figure 1. Remodeling of the intestine during Xenopus laevis metamorphosis. Cross sections of the intestine from animals at premetamorphic (stage 54), metamorphic climax (stage 60), and the end of metamorphosis (stage 66) 68 were stained with pyronin Y and methyl green to show the morphology. The strong pyronin Y signals observed at metamorphic climax indicate islets of proliferating adult epithelial cells. Scale bars are 100 mm.
Figure 2. Regulation of MMP expression by TH in Xenopus laevis . Tadpoles at premetamorphic stage, i.e., stage 54, were treated with 5 nM T3 (3, 5, 3� triiodothyronine, the more active form of the two naturally occurring TH) to induce metamorphosis. The animals were sacrificed and RNA was isolated from the intestines after 0 to 4 days of T3 treatment and used for total RNA isolation with TRIzol reagent. The RNA was made DNA free and subjected to RT-PCR to analyze the expression of the MMPs with the ribosome protein L8 (rpL8) gene as the control.
Figure 3. Spatial localization of MT1-MMP and GelA mRNAs in the intestine at metamorphic climax. Cross sections of intestine from animals at metamorphic climax (stage 62) were examined for MT1-MMP (A and B) and GelA (c and d) expression by in situ hybridization. Dark blue deposits indicate the sites of probe binding. b, d: Higher magnification images of a boxed area in panels A and C, respectively. MT1-MMP is expressed in the connective tis- sue (CT) and longitudinal muscle layer (LM) but not in epithelium (EP), circular muscle layer (CM) and serosa (S), while GelA is exclusively expressed in CT. Ty, typhlosole. Scale bars are 100 mm (A and C) and 50 mm (B and D) (see ref. 56 for details).
Figure 5. Precocious expression of ST3 leads to epithelial cell death in premetamorphic tadpoleintestine. Transgenic tadpoles expressing wild type (ST3) or catalytically inactive ST3 (ST3m) were reared to premetamorphic stage 54 and then subjected to daily heat shock for four days. Cross section of the intestine were isolated and subjected to TUNEL labeling to detect apoptotic cells, which were found in the epithelium (EP) of animals expression ST3 but not ST3m. Lu, intestinal lumen (see ref. 62 for details).
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