Abstract
Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca2+ and dephosphorylated NFATc2 under low Ca2+ levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development.
Highlights
The hair follicle is a highly developed organ and the mechanisms that regulate the hair cycle have been extensively investigated [1,2]. Immunosuppressant drugs such as cyclosporin A (CsA) and FK506, which are indispensable for transplantation, cause hypertrichosis [1,3]; recent studies have shown that this phenomenon is associated with inhibition of the calcineurin (Cn)/ nuclear factor of activated T cells (NFAT) signaling pathway in follicular keratinocytes and follicular stem cells [4,5]
We found that cyclin G2, an atypical cyclin that correlates with cell cycle arrest, was regulated by CnAß-FK/ NFATc2 [18,19]
These results suggested that the atypical CnAß might be expressed in hair follicles but not in the epidermis
Summary
The hair follicle is a highly developed organ and the mechanisms that regulate the hair cycle have been extensively investigated [1,2]. Immunosuppressant drugs such as cyclosporin A (CsA) and FK506, which are indispensable for transplantation, cause hypertrichosis [1,3]; recent studies have shown that this phenomenon is associated with inhibition of the calcineurin (Cn)/ nuclear factor of activated T cells (NFAT) signaling pathway in follicular keratinocytes and follicular stem cells [4,5]. In bulge stem cells, NFATc1 regulates proliferation of follicular stem cells through Cdk repression [5]
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