The research in the Unit of Molecular Morphogenesis is focussed on the understanding of the molecular mechanism of amphibian metamorphosis. The control of this developmental process by thyroid hormone (TH) offers a unique paradigm in which to study genes that are important for post-embryonic organ development. We began to study metamorphosis by choosing the remodeling of the tadpole intestine in Xenopus laevis as a model system. The tadpole intestine is a simple tubular structure consisting of primarily a single layer of primary epithelial cells. During metamorphosis, it is transformed into a multiply folded adult epithelium with elaborate connective tussue and muscles through specific cell death and selective all proliferation and differentiation. We have many TH-response genes in the intestine during this transition. Among them are genes encoding matrix metalloproteinases (MMPs) and a putative morphogen, the Xenopus hedgehog. Thus, a major area of our work is to understand how these extracellular proteins influence organogenesis. Our evidence suggests that the Xenopus hedgehog functions in initiating and/or stimulating adult intestinal epithelial all proliferation and differentiation, in agreement with its morphogenic roles in other species. On the other hand, MMPs appear to be involved in ECM remodeling, which in turn influences cell behavior, especially larval epithelial apoptosis and adult cell proliferation. We have developed in vitro cell and organ culture systems which will allow us to further investigate how these proteins function to regulate cell-cell and cell-ECM interactions. The second research area aims at investigating the function of thyroid hormone receptors (TRs) during metamorphosis. Our current work has demonstrated that TR/RXR (9-cis retinoic acid receptor) can function within a chromatin context and that transcriptional activation leads to chromatin disruption. We have revealed a number of interesting characteristic associated with TR function. In addition, we have identified and functionally characterized a mutant TR in Xenopus laevis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Intramural Research (Z01)
Project #
1Z01HD001901-02
Application #
2575718
Study Section
Special Emphasis Panel (LME)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1996
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Ishizuya-Oka, Atsuko; Hasebe, Takashi; Shi, Yun-Bo (2010) Apoptosis in amphibian organs during metamorphosis. Apoptosis 15:350-64
Matsuda, Hiroki; Shi, Yun-Bo (2010) An essential and evolutionarily conserved role of protein arginine methyltransferase 1 for adult intestinal stem cells during postembryonic development. Stem Cells 28:2073-83
Mathew, Smita; Fu, Liezhen; Hasebe, Takashi et al. (2010) Tissue-dependent induction of apoptosis by matrix metalloproteinase stromelysin-3 during amphibian metamorphosis. Birth Defects Res C Embryo Today 90:55-66
Matsuda, Hiroki; Paul, Bindu D; Choi, Cheol Young et al. (2009) Novel functions of protein arginine methyltransferase 1 in thyroid hormone receptor-mediated transcription and in the regulation of metamorphic rate in Xenopus laevis. Mol Cell Biol 29:745-57
Heimeier, Rachel A; Das, Biswajit; Buchholz, Daniel R et al. (2009) The xenoestrogen bisphenol A inhibits postembryonic vertebrate development by antagonizing gene regulation by thyroid hormone. Endocrinology 150:2964-73
Shi, Yun-Bo (2009) Dual functions of thyroid hormone receptors in vertebrate development: the roles of histone-modifying cofactor complexes. Thyroid 19:987-99
Fiorentino, Maria; Fu, Liezhen; Shi, Yun-Bo (2009) Mutational analysis of the cleavage of the cancer-associated laminin receptor by stromelysin-3 reveals the contribution of flanking sequences to site recognition and cleavage efficiency. Int J Mol Med 23:389-97
Hasebe, Takashi; Kajita, Mitsuko; Shi, Yun-Bo et al. (2008) Thyroid hormone-up-regulated hedgehog interacting protein is involved in larval-to-adult intestinal remodeling by regulating sonic hedgehog signaling pathway in Xenopus laevis. Dev Dyn 237:3006-15
Wang, Xuedong; Matsuda, Hiroki; Shi, Yun-Bo (2008) Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis. Endocrinology 149:5610-8
Wang, Di; Guo, Ming-Xiong; Hu, Hai-Ming et al. (2008) Human T-cell leukemia virus type 1 oncoprotein tax represses ZNF268 expression through the cAMP-responsive element-binding protein/activating transcription factor pathway. J Biol Chem 283:16299-308

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