# Foxn1 Control of Skin Function
## 3 Foxn1 Regulates Epidermis and Hair Follicle Physiology
The activation of Foxn1 in primary human keratinocytes [39] and primary nude mouse keratinocytes [46] caused an increase in phospholipase 81 (PLC81, 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1) mRNA [39] and protein levels [46]. Stimulated by Foxn1, an increase in the level of PLC61, the key molecule in the phosphoinositide signaling pathway, further supports the role of Foxn1 in PKC [58] and AKT [39] signaling. Moreover, a study by [PERSON] showed that PLC81 KO mice displayed a nude phenotype similar to Foxn1\({}^{-/-}\) mice and that the expression of PLC81 was induced in Foxn1-transfected cells, indicating that PLC81 is a molecule downstream of Foxn1 [59]. The broad range of Foxn1 functions in the epidermis is also delineated in its role in the pigmentation process. Foxn1 stimulates epithelial cells to release fibroblast growth factor 2 (Fgf2), a signal that is recognized by melanocytes for pigment transfer to Foxn1-positive cells [38; 60]. The multiple effects of Foxn1 on epidermal physiology were also analysed through proteomic profiling of cultured keratinocytes transfected with Ad-Foxn1 [46]. A proteomics analysis identified proteins that can act as factors controlling the balance between cell proliferation, differentiation, and apoptosis in response to Foxn1. Interestingly, control (Ad-GFP transduced) keratinocytes were characterized by the presence of pro-survival proteins. 3-phosphooinositide-dependent protein kinase 1 (Pdpk1), the protein that acts upstream of the Akt (protein kinase B) pathway, and Hsp-90 and -27 proteins have been shown to be involved in pro-proliferative and pro-survival pathways, respectively. In contrast, some of the proteins detected in Foxn1-overexpressing keratinocytes are related to pro-apoptotic functions, such as prolyl 4-hydroxylase, beta polypeptide (P4 hb), galectin-7 (Lgals7), and voltage-dependent anion-selective channel protein 1 (Vdac1). Furthermore, flow cytometry analysis revealed an increase in apoptotic cells in the Ad-Foxn1 population [46]. However, the most striking results of proteomic analysis point to Foxn1 as a factor regulating the levels of proteins (i.e., thioredoxin and prolyl 4-hydroxylase) involved in adaptation to normoxic/hypoxic conditions [46]. Interestingly, the comparison between the skin transcriptomes of Foxn1\({}^{\
icefrac{{-}}{{-}}}\) and Foxn1\({}^{\
icefrac{{+}}{{+}}}\) mice revealed considerable differences in the genes associated with skin immuno- and proteolytic-defense [47]. As expected, compared to that of Foxn1\({}^{\
icefrac{{+}}{{+}}}\) mice, the skin of Foxn1\({}^{\
icefrac{{-}}{{-}}}\) mice displayed downregulated transcripts of CD3 (T lymphocytes). In contrast, Foxn1\({}^{\
icefrac{{-}}{{-}}}\) mouse skin showed upregulation of the transcripts of proteolytic molecules such as kallikreins and kallikrein-related peptidases, including Klk 6, Klk13, Klk7, Klk8, and Klk10, protease serine 27 (Prss27), which is involved in the skin barrier proteolytic cascade, and langerin (CD207, marker of dendritic cells), among others [47; 61]. These data broaden the potential range of Foxn1 action in the skin but may also indicate the presence of a compensatory mechanism that already exists at the transcriptome level that provides a form of protection in nude mice as described by [PERSON] [62]. Considering that the major locations of Foxn1 are confined to the epithelium of the two immunocompetent organs, the thymus and the skin, the role of Foxn1 in the immunodefense guard in the skin has gained little interest [63]. Taken together, these investigations underline the multiple, both direct and indirect, effects of Foxn1 on the skin, particularly its epidermal layer.