Requirement of zinc transporter ZIP10 for epidermal development: Implication of the ZIP10–p63 axis in epithelial homeostasis

Abstract

Skin tissues, in particular the epidermis, are severely affected by zinc deficiency. However, the zinc-mediated mechanisms that maintain the cells that form the epidermis have not been established. Here, we report that the zinc transporter ZIP10 is highly expressed in the outer root sheath of hair follicles and plays critical roles in epidermal development. We found that ZIP10 marked epidermal progenitor cell subsets and that ablating caused significant epidermal hypoplasia accompanied by down-regulation of the transactivation of p63, a master regulator of epidermal progenitor cell proliferation and differentiation. Both ZIP10 and p63 are significantly increased during epidermal development, in which ZIP10-mediated zinc influx promotes p63 transactivation. Collectively, these results indicate that ZIP10 plays important roles in epidermal development via, at least in part, the ZIP10-zinc-p63 signaling axis, thereby highlighting the physiological significance of zinc regulation in the maintenance of skin epidermis.

The epithelial zinc transporter ZIP 10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity

“…Treatment of human epidermal keratinocytes with scrambled control or siRNA targeting SLC39A6 (encoding ZIP6), which is similar to SLC39A10 in its structure and function, did not affect epidermal differentiation in the reconstituted human skin model (Fig. a), similar to results observed for Zip6 knockout mice . However, KD of ZIP10 by SLC39A10 siRNA treatment in keratinocytes severely disturbed epidermal formation (Fig.…”

“…As HATs normally function as coactivators for TFs, we wondered whether the TFs that are affected by ZIP10 may be functionally and physically associated with HATs. Previously, a set of TFs related to the upregulation of genes in a ZIP10‐dependent manner was analysed . To examine whether these TFs were more associated with HATs than ZIP10‐independent TFs (Table S1; see Supporting Information), we calculated the ratio of the ZIP10‐dependent or ‐independent TFs interacting with HATs.…”

“…It is well established that zinc is important for genomic stability, and zinc deficiency causes epigenetic alterations . ZIP10 is a crucial zinc transporter for epidermal development and also remains a major epidermal ZIP transporter in adult skin, based on analyses of conditional knockout mice . Therefore, it is reasonable to hypothesize that an alteration of ZIP10‐mediated cytosolic zinc homeostasis could disturb the expression of genes involved in epidermal differentiation of adult skin by changing the activity of epigenetic enzymes.…”

“…Recent advances have shown that several ZIP proteins, particularly ZIP4, ZIP7, ZIP10 and ZIP13, play an important role in murine and human skin . Among them, ZIP10 is a crucial zinc transporter in murine epidermal development that supplies zinc to support the increased activity of elevated p63 levels starting at embryonic day 14, when epidermal progenitor cells proliferate vigorously to form stratified mature epidermis . Therefore, the regulated expression of p63 and ZIP10 has been suggested to be essential during epidermal morphogenesis, highlighting the importance of zinc uptake during embryonic development of the skin epidermis.…”

FIH‐1 engages novel binding partners to positively influence epithelial proliferation via p63

“…Among them, ΔNp63α 1 is the main isoform in proliferating keratinocytes 2 and thought to be obligatory for proper development of epithelial structures. 6 Although much is known about the genes regulated by p63 in keratinocytes and the epidermis, [9][10][11] how p63 is regulated is less clear. 2,5 Furthermore, ΔNp63 prevents Notch signaling, which inhibits p21 expression, thereby retarding epidermal differentiation.…”