Requirement of Zinc Transporter SLC39A7/ZIP7 for Dermal Development to Fine-Tune Endoplasmic Reticulum Function by Regulating Protein Disulfide Isomerase

  • J Invest Dermatol. 2017 Aug;137(8):1682-1691. doi: 10.1016/j.jid.2017.03.031.
Bum-Ho Bin  1 ,  Jinhyuk Bhin  2 ,  Juyeon Seo  3 ,  Se-Young Kim  4 ,  Eunyoung Lee  4 ,  Kyuhee Park  5 ,  Dong-Hwa Choi  5 ,  Teruhisa Takagishi  6 ,  Takafumi Hara  6 ,  Daehee Hwang  2 ,  Haruhiko Koseki  7 ,  Yoshinobu Asada  8 ,  Shinji Shimoda  9 ,  Kenji Mishima  10 ,  Toshiyuki Fukada  11
Affiliations
  • 1. Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan. Electronic address: [email protected].
  • 2. Department of New Biology, DGIST, Daegu, Republic of Korea.
  • 3. Amorepacific R&D Unit, Beauty in Longevity Science Research Division, Beauty Food Research Team, Yongin, Republic of Korea.
  • 4. Department of Biotechnology, Korea University, Seoul, Republic of Korea.
  • 5. Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea.
  • 6. Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
  • 7. Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 8. Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan.
  • 9. Department of Oral Anatomy-1, Tsurumi University School of Dental Medicine, Yokohama, Japan.
  • 10. Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan.
  • 11. Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan; Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address: [email protected].
PMID: 28545780 DOI: 10.1016/j.jid.2017.03.031
Abstract

Skin is the first area that manifests zinc deficiency. However, the molecular mechanisms by which zinc homeostasis affects skin development remain largely unknown. Here, we show that zinc-regulation transporter-/iron-regulation transporter-like protein 7 (ZIP7) localized to the endoplasmic reticulum plays critical roles in connective tissue development. Mice lacking the Slc39a7/Zip7 gene in Collagen 1-expressing tissue exhibited dermal dysplasia. Ablation of ZIP7 in mesenchymal stem cells inhibited cell proliferation thereby preventing proper dermis formation, indicating that ZIP7 is required for dermal development. We also found that mesenchymal stem cells lacking ZIP7 accumulated zinc in the endoplasmic reticulum, which triggered zinc-dependent aggregation and inhibition of protein disulfide isomerase, leading to endoplasmic reticulum dysfunction. These results suggest that ZIP7 is necessary for endoplasmic reticulum function in mesenchymal stem cells and, as such, is essential for dermal development.