title: A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling.
abstract: BACKGROUND
  Intestinal remodeling during amphibian metamorphosis has long been studied as a model for the formation of the adult organs in vertebrates, especially the formation of adult organ-specific stem cells. Like all other processes during metamorphosis, this process is controlled by thyroid hormone (T3), which affects cell fate and behavior through transcriptional regulation of target genes by binding to T3 receptors (TRs). Earlier studies have shown that Sonic hedgehog (Shh) is induced by T3 in the developing adult stem cells and that the Shh receptor and other downstream components are present in the connective tissue and at lower levels in the muscles at the climax of intestinal remodeling. However, no in vivo studies have carried out to investigate whether Shh produced in the adult cells can regulate the connective tissue to promote intestinal maturation.
  
  
  RESULTS
  We have addressed this issue by treating tadpoles with Shh inhibitor cyclopamine. We showed that cyclopamine but not the structurally related chemical tomatidine inhibited the expression of Shh response genes BMP4, Snai2, and Twist1. More importantly, we showed that cyclopamine reduced the cell proliferation of both the developing adult stem cells as well as cells in the other intestinal tissues at the climax of metamorphosis, leading to delayed/incomplete remodeling of the intestine at the end of metamorphosis. We further revealed that both Snai2 and Twist1 were strongly upregulated during metamorphosis in the intestine and their expression was restricted to the connective tissue.
  
  
  CONCLUSIONS
  Our results suggest that Shh indeed signals the connective tissue whereby it can increase adult stem cell proliferation and promote formation of the adult intestine.
authors: Section on Molecular Morphogenesis, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18 T, Rm. 106, Bethesda, MD 20892 USA.
authors: Luan
authors: L
authors: Wen
authors: Department of Biology, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023 Japan.
authors: Takashi
authors: T
authors: Hasebe
authors: Section on Molecular Morphogenesis, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18 T, Rm. 106, Bethesda, MD 20892 USA.
authors: Thomas C
authors: TC
authors: Miller
authors: Department of Biology, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023 Japan.
authors: Atsuko
authors: A
authors: Ishizuya-Oka
authors: Section on Molecular Morphogenesis, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 18 T, Rm. 106, Bethesda, MD 20892 USA.
authors: Yun-Bo
authors: YB
authors: Shi
keywords: Adult stem cells; Amphibian metamorphosis; Postembryonic development; Thyroid hormone receptor; Xenopus laevis