title: Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress.
abstract: Zinc transporters play a critical role in spatiotemporal regulation of zinc homeostasis. Although disruption of zinc homeostasis has been implicated in disorders such as intestinal inflammation and aberrant epithelial morphology, it is largely unknown which zinc transporters are responsible for the intestinal epithelial homeostasis. Here, we show that Zrt-Irt-like protein (ZIP) transporter ZIP7, which is highly expressed in the intestinal crypt, is essential for intestinal epithelial proliferation. Mice lacking Zip7 in intestinal epithelium triggered endoplasmic reticulum (ER) stress in proliferative progenitor cells, leading to significant cell death of progenitor cells. Zip7 deficiency led to the loss of Olfm4+ intestinal stem cells and the degeneration of post-mitotic Paneth cells, indicating a fundamental requirement for Zip7 in homeostatic intestinal regeneration. Taken together, these findings provide evidence for the importance of ZIP7 in maintenance of intestinal epithelial homeostasis through the regulation of ER function in proliferative progenitor cells and maintenance of intestinal stem cells. Therapeutic targeting of ZIP7 could lead to effective treatment of gastrointestinal disorders.
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.|Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Ohashi
authors.affiliation: Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iwanaga
authors.affiliation: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.|Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Furusawa
authors.affiliation: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Tarou
authors.initials: T
authors.lastname: Irié
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Nagahama Institute of Bio-Science and Technology, Tamura, Nagahama, Shiga, Japan.
authors.forename: Atsushi
authors.identifier: http://orcid.org/0000-0003-4297-8368
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hara
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.|Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Gastroenterology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Equipe de Morphogenese et Signalisation cellulaires UMR 144 CNRS/Institut Curie, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Division of Stem Cell Cellomics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0002-7497-4188
authors.initials: H
authors.lastname: Watarai
authors.affiliation: Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mishima
authors.affiliation: Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
authors.affiliation: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.|Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hase
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.|Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan.|Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000254:growth & development / Q000378:metabolism; D055786:Gene Knockout Techniques; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D009940:Organoids / Q000254:growth & development; D019879:Paneth Cells / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D015032:Zinc; C000589478:Slc39a7 protein, mouse