# Foxn1 Control of Skin Function
## 3 Foxn1 Regulates Epidermis and Hair Follicle Physiology
These data suggest that the lack of Foxn1 (Foxn1\({}^{-/-}\)) maintains the skin of adult (nude) mice in an undeveloped state, which is a rare example of neoteny phenomenon [47]. Presumably, these features of Foxn1\({}^{-/-}\) (nude) mice permit regenerative skin wound healing, as was observed for mouse embryos at up to 16.5 days of development [49; 50; 51]. Among genes that are exclusively related to Foxn1\({}^{-/-}\) deficiency in adult skin, members of the Wnt, Bmp, and Notch families were significantly altered [47]. Genes of the Notch group (Notch2 and 4 receptors, Notch ligands: Dll1, Dll4, and Dlk1) and several genes in the bone morphogenetic protein (Bmp) family (_Bmp2_ and _Bmp4_, receptor Bmpr1b) in the skin of Foxn1\({}^{-/-}\) mice were downregulated. In contrast, most of the members of Wnt family genes, namely, the Wnt ligands Wisp2, Wnt10a, and Wnt11, the Wnt mediator \(\beta\)-catenin (Ctnnb1) and Wnt receptors frizzled 1 (Fzd1) and frizzled 6 (Fzd6), were upregulated in the skin of Foxn1\({}^{-/-}\) mice with concurrently  
Figure 1: Foxn1 expression in the skin of Foxn1::eGFP mice. hf-hair follicles, arrows indicate Foxn1 positivity in the epidermis. downregulated Wnt pathway inhibitors, namely, dickkopf 1 (Dkk1), frizzled-related protein (Frzb), and secreted frizzled-related protein 2 (Sfrp2) [47]. The participation of Wnt signaling in the regulation of Foxn1 expression has been observed in the thymus [52], but little is known about epidermal Foxn1 regulation. [PERSON] et al. showed that Wnt5a is a direct Notch signaling target in dermal papilla cells, with Foxn1 acting as a downstream target in keratinocytes [53]. [PERSON] et al. demonstrated that Foxn1 and Msc2, which function downstream of Bmp4 signaling, are required for the maintenance of Notch1 expression during the development of hair follicles [54]. A study by [PERSON] et al., initially based on phenotypic similarities between Foxn1\({}^{-/-}\) and Hoxc13\({}^{-/-}\) mice due to their nude appearance and nail development, defects points to HOXC13-dependent activation of Foxn1 in the control of hair follicles and nail differentiation [55]. However, regulators of Foxn1 activity, particularly in the interfollicular part of the epidermis, are largely unidentified. Although Foxn1 function in the skin and hair follicles has been analysed in wild-type mice as well as consequences of the defects caused by Foxn1 deficiency in nude mice, the precise role of Foxn1 in skin physiology and its target genes are still unclear. It has been shown that Foxn1 regulates the expression of hair keratin genes, particularly mHa3 and mHa5 [42; 56; 57]. HeLa cells (human epithelial cells that do not express hair keratins) transfected with the Foxn1 gene showed strong induction of mHa3, mHb3, and mHb5 by Foxn1 stimulation [56]. However, transient activation of Foxn1 in keratinocytes followed by gene microarray analyses did not show any keratin gene regulation due to Foxn1 stimulation [39]. In contrast, proteomics analysis of primary keratinocytes obtained from nude mice (Foxn1\({}^{-/-}\)) and transduced with Ad-Foxn1 showed upregulation of type II keratin 5 and Krt6b protein due to Foxn1 expression [46]. The prominent upregulation of some keratin (Krt) genes (_Krt23_, -73, -82, -16, and -17) in the total skin and Krt6a and -6b in the epidermis of Foxn1\({}^{-/-}\) (nude) mice was also reported [46]. The stimulatory effect of Foxn1 on the first steps of the keratinocyte differentiation program and its suppressive effect on the late stages was examined in detail in primary keratinocyte cultures [58]. The study revealed that the transcriptional activity of Foxn1 can be mediated through indirect mechanisms. Protein kinase C (PKC) has been identified as a key target of Foxn1 during the keratinocyte differentiation program. Applying loss and gain of Foxn1 function methodology showed that inactivation of Foxn1 stimulates PKC protein levels, whereas its overexpression reduces PKC signaling [58].