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PLoS Genet. 2016 Oct 13;12(10):e1006349. doi: 10.1371/journal.pgen.1006349. eCollection 2016 Oct.

Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress.

Author information

1
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
2
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
3
Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
4
Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
5
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.
6
Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan.
7
Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
8
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
9
Nagahama Institute of Bio-Science and Technology, Tamura, Nagahama, Shiga, Japan.
10
Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Japan.
11
Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.
12
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
13
Department of Gastroenterology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
14
Equipe de Morphogenese et Signalisation cellulaires UMR 144 CNRS/Institut Curie, Paris, France.
15
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.
16
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.

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.

PMID:
27736879
PMCID:
PMC5065117
DOI:
10.1371/journal.pgen.1006349
[Indexed for MEDLINE]
Free PMC Article

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