title: Mechanistic target of rapamycin complex 1 signaling regulates cell proliferation, cell survival, and differentiation in regenerating zebrafish fins.
abstract: BACKGROUND
  The mechanistic target of rapamycin complex1 (mTORC1) signaling pathway has been implicated in functions of multicellular processes, including cell growth and metabolism. Although recent reports showed that many signaling pathways, including Activin, Bmp, Fgf, sonic hedgehog, Insulin-like growth factor (IGF), Notch, retinoic acid, and Wnt, are implicated in non-mammalian vertebrate regeneration, also known as epimorphic regeneration, mTORC1 function remains unknown.
  
  
  RESULTS
  To investigate the role of mTORC1 signaling pathway in zebrafish caudal fin, we examined the activation and function of mTORC1 signaling using an antibody against phosphorylated S6 kinase and a specific inhibitor, rapamycin. mTORC1 signaling is activated in proliferative cells of intra-ray and wound epidermal cells before blastema formation, as well as in proliferative blastema cells, wound epidermal cells, and osteoblasts during regenerative outgrowth. Before blastema formation, proliferation of intra-ray and wound epidermal cells is suppressed, but cell death is not affected by mTORC1 signaling inhibition with rapamycin. Moreover, rapamycin treatment inhibits blastema and wound epidermal cell proliferation and survival during blastema formation and regenerative outgrowth, as well as osteoblast proliferation and differentiation during regenerative outgrowth. We further determined that mTORC1 signaling is regulated through IGF-1 receptor/phosphatidylinositol-3 kinase and Wnt pathways during fin regeneration.
  
  
  CONCLUSIONS
  Taken together, our findings reveal that mTORC1 signaling regulates proliferation, survival, and differentiation of intra-ray cells, wound epidermis, blastema cells, and/or osteoblasts in various fin regeneration stages downstream of IGF and Wnt signaling pathways.
authors.affiliation: Department of Biological Science, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. hirosekentaro@hiroshima-u.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Department of Biological Science, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. m143633@hiroshima-u.ac.jp.
authors.forename: Taishi
authors.initials: T
authors.lastname: Shiomi
authors.affiliation: Department of Biological Science, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. hozumish@hiroshima-u.ac.jp.
authors.forename: Shunya
authors.initials: S
authors.lastname: Hozumi
authors.affiliation: Department of Biological Science, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. yutaka@hiroshima-u.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kikuchi
mesh_terms: D058500:Animal Fins / Q000166:cytology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012038:Regeneration; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000502:physiology; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D029961:Zebrafish Proteins