Bin Bum-Ho, Bhin Jinhyuk, Seo Juyeon, Kim Se-Young, Lee Eunyoung, Park Kyuhee, Choi Dong-Hwa, Takagishi Teruhisa, Hara Takafumi, Hwang Daehee, Koseki Haruhiko, Asada Yoshinobu, Shimoda Shinji, Mishima Kenji, Fukada Toshiyuki
Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan.
Department of New Biology, DGIST, Daegu, Republic of Korea.
J Invest Dermatol. 2017 Aug;137(8):1682-1691. doi: 10.1016/j.jid.2017.03.031. Epub 2017 May 22.
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.
皮肤是最早表现出锌缺乏的部位。然而，锌稳态影响皮肤发育的分子机制在很大程度上仍不清楚。在此，我们表明定位于内质网的锌调节转运蛋白/铁调节转运蛋白样蛋白7（ZIP7）在结缔组织发育中起关键作用。在表达胶原蛋白1的组织中缺乏Slc39a7/Zip7基因的小鼠表现出皮肤发育异常。间充质干细胞中ZIP7的缺失抑制了细胞增殖，从而阻止了正常真皮的形成，表明ZIP7是真皮发育所必需的。我们还发现，缺乏ZIP7的间充质干细胞在内质网中积累锌，这引发了锌依赖性聚集并抑制了蛋白质二硫键异构酶，导致内质网功能障碍。这些结果表明，ZIP7对间充质干细胞中的内质网功能是必需的，因此对真皮发育至关重要。
