| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
During amphibian metamorphosis, the larval epithelium in the digestive tract undergoes apoptosis, whereas the adult epithelium that originates from stem cells actively proliferates and differentiates into the epithelium similar to the mammalian counterpart. The remodeling process includes epithelial-connective tissue interactions and can be triggered by a single hormone, thyroid hormone (TH). In this study, we aimed to clarify molecular mechanisms underlying the remodeling of the digestive tract through the analyses of TH response genes that have been recently cloned from the Xenopus laevis intestine. First, to assess possible functions of the TH response genes, we examined the relationships between their expression pattern and morphological changes at the cellular level, by using in situ hybridization and immunohistochemistry. We found that stromelysis-3, a matrix metalloproteinase (MMP), gene is the only one whose expression is connective tissue-specific and spatio-temporally correlates well with the larval epithelial apoptosis, whereas me epithelial-specific expression of sonic hedgehog (Shh) correlates with active proliferation of adult epithelial stem cells. Next, to clarify functions of ST3 gene in the epithelial apoptosis, we performed organ cultures arid demonstrated that addition of a function-blocking antibody against Xenopus ST3 to the culture medium inhibits TH-induced apoptosis of the larval epithelium, but has little effect on the adult epithelial proliferation on the other hand, addition of Shh to the culture medium activates cell proliferation but inhibits differentiation of the adult epithelium. In addition, we have shown that Shh induces the expression of bone morphogenic protein-4 (BMP-4) in the connective tissue and that BMP-4 receptor mRNA is expressed in the developing adult epithelium. Future studies should be more directed towards functional analysis of Shh/BMP-4 signaling.
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