Abstract
Two mesenchymal zinc transporters, ZIP7 and ZIP13, play critical roles in dermal development. ZIP7 and ZIP13 are the closest among the conserved mammalian zinc transporters. However, whether their functions are complementary remains a controversial issue. In the present study, we found that the expression of ZIP13, but not ZIP7, is elevated by transforming growth factor beta (TGF-β) treatment, indicating that TGF-β-mediated ZIP13 amplification is crucial for collagen production during dermal development. Genome-wide gene expression analysis revealed that ~26% of genes are dependent on either ZIP7 or ZIP13, which is greater than the ~17% of genes dependent on both of them. ZIP7 depletion induces endoplasmic reticulum (ER) stress in mesenchymal stem cells, resulting in significant inhibition of fibrogenic differentiation. However, ZIP13 depletion does not induce ER stress. Though both ZIP7 and ZIP13 contain traditional ER signal peptides for their intracellular localization, their distributions are distinct. When ZIP7 and ZIP13 are coexpressed, their localizations are distinct; ZIP7 is located on the ER, but ZIP13 is located on both the ER and Golgi, indicating that only ZIP13 is a zinc gatekeeper on the Golgi. Our data illustrate that the different actions of ZIP7 and ZIP13 are crucial for dermal development.
Highlights
Zinc is an essential trace mineral in the skin, and many clinical reports have demonstrated that the skin is the first area that manifests zinc deficiency [1,2,3,4]
The mRNA expression level of SMAD7 fluctuated during embryo development; its expression was high at E7 and E14 but low at E11 and E17, which is similar to the expression levels of ZIP7 and ZIP13 but not Col1a2 (Figure 1A), implying that zinc transporters are associated with TGF-β signaling
We found that treatment of human mesenchymal stem cells with TGF-β induced mRNA expression of ZIP13 as MSX2 and SMAD7, which are well-known TGF-β–SMAD target genes (Figure 1B) [17]
Summary
Zinc is an essential trace mineral in the skin, and many clinical reports have demonstrated that the skin is the first area that manifests zinc deficiency [1,2,3,4]. ZIP7 and ZIP13, the critical zinc transporters during dermis development [16,17], are classified in the LIV-1 subfamily, whose members are present in only eukaryotic cells and possess the HEXXH motif, a putative zinc-binding motif [12]. Though both ZIP7 and ZIP13 transport zinc and are involved in zinc homeostasis as intracellular zinc transporters [16,17], their precise cellular locations remain controversial. We found that the transforming growth factor beta (TGF-β)–SMAD–ZIP13 axis is crucial for dermal formation
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