title: Thyroid Hormone-Induced Activation of Notch Signaling is Required for Adult Intestinal Stem Cell Development During Xenopus Laevis Metamorphosis.
abstract: In Xenopus laevis intestine during metamorphosis, the larval epithelial cells are removed by apoptosis, and the adult epithelial stem (AE) cells appear concomitantly. They proliferate and differentiate to form the adult epithelium (Ep). Thyroid hormone (TH) is well established to trigger this remodeling by regulating the expression of various genes including Notch receptor. To study the role of Notch signaling, we have analyzed the expression of its components, including the ligands (DLL and Jag), receptor (Notch), and targets (Hairy), in the metamorphosing intestine by real-time reverse transcription-polymerase chain reaction and in situ hybridization or immunohistochemistry. We show that they are up-regulated during both natural and TH-induced metamorphosis in a tissue-specific manner. Particularly, Hairy1 is specifically expressed in the AE cells. Moreover, up-regulation of Hairy1 and Hairy2b by TH was prevented by treating tadpoles with a γ-secretase inhibitor (GSI), which inhibits Notch signaling. More importantly, TH-induced up-regulation of LGR5, an adult intestinal stem cell marker, was suppressed by GSI treatment. Our results suggest that Notch signaling plays a role in stem cell development by regulating the expression of Hairy genes during intestinal remodeling. Furthermore, we show with organ culture experiments that prolonged exposure of tadpole intestine to TH plus GSI leads to hyperplasia of secretory cells and reduction of absorptive cells. Our findings here thus provide evidence for evolutionarily conserved role of Notch signaling in intestinal cell fate determination but more importantly reveal, for the first time, an important role of Notch pathway in the formation of adult intestinal stem cells during vertebrate development. Stem Cells 2017;35:1028-1039.
authors.affiliation: Department of Biology, Nippon Medical School, Musashino, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hasebe
authors.affiliation: Department of Biology, Nippon Medical School, Musashino, Tokyo, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Department of Molecular Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Kajita
authors.affiliation: Section on Molecular Morphogenesis, Cell Regulation and Development Affinity Group, Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Liezhen
authors.initials: L
authors.lastname: Fu
authors.affiliation: Section on Molecular Morphogenesis, Cell Regulation and Development Affinity Group, Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Yun-Bo
authors.initials: YB
authors.lastname: Shi
authors.affiliation: Department of Biology, Nippon Medical School, Musashino, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ishizuya-Oka
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006965:Hyperplasia; D007422:Intestines / Q000166:cytology*; D008675:Metamorphosis, Biological / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013963:Thyroid Hormones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000235:genetics / Q000254:growth & development*
chemical_list: D003984:Dibenzazepines; D012333:RNA, Messenger; D051880:Receptors, Notch; D013963:Thyroid Hormones; D029867:Xenopus Proteins; C527817:dibenzazepine
keywords: Amphibian metamorphosis; Epithelial stem cell; Intestinal remodeling; Notch signaling; Thyroid hormone