# Foxn1 Control of Skin Function
## 4 Foxn1 as a Skin Wound Healing Regulator  
The first premise that Foxn1 may regulate the skin wound healing process came from experiments performed on Foxn1\({}^{\
icefrac{{-}}{{-}}}\) mice [64; 65; 66; 67]. Foxn1 deficiency resulted in an unusual skin wound healing process in nude mice. While scar forming wound healing (reparative healing) is generally characteristic of mammals, nude mice appear to be remarkable in scar-less (regenerative) healing. Until that discovery, regenerative skin wound healing was detected exclusively in mammalian fetuses, although it was limited to the first two trimesters of intrauterine life [68]. Injury generated after the so-called transitional period, which takes place after the first two trimesters and before the third and last trimester of gestation, resulted in scar-forming skin healing observed in adults [51]. The analysis of post-injured skin of Foxn1\({}^{\
icefrac{{-}}{{-}}}\) and Foxn1\({}^{\
icefrac{{+}}{{+}}}\) mice has attracted some interest [65]. Low levels of Mmp9 expression in the epidermis of Foxn1\({}^{\
icefrac{{-}}{{-}}}\) mice compared to high levels of Mmp9 expression in the total skin content have been reported [47]. Since low epidermal expression of Mmp9 coincided with epidermal Foxn1 deficiency in nude mice, it seemed conceivable that there is a direct interaction between them. So far, there are no data that may support the direct link between those two factors. However, it was shown that both Mmp9 and Foxn1 expression in keratinocytes is stimulated by hypoxic conditions [46]. All of the above features characterize the scar-free healing process detected in skin injuries of mammalian fetuses. Interestingly, the transition from scar-free to scar-forming healing during in utero life in mouse fetuses coincides with skin Foxn1 appearance, which takes place at embryonic day 16.5. It is conceivable that Foxn1 stimulates skin development and initiates the transition between scar-free and scar-forming skin wound healing during intrauterine life. This hypothesis is still under investigation [40]. A study that aimed to analyze the role of Foxn1 in skin wound healing was performed on transgenic Foxn1::EGFP mice [43; 44; 46; 69]. Post-bounded skin of Foxn1::EGFP mice showed the accumulation of cells bearing an eGFP (Foxn1) signal around the wound (wound margin) and in cells forming the leading epithelial tongue migrating underneath the scab. The entire extent and thickness of the migrating epithelium showed co-localization of Foxn1-eGFP with keratin 16 (a marker of activated, hyperproliferative epithelia; Figure 2) or with E-cadherin (a marker of epidermal cell characteristics; [43; 44]). However, the presence of Foxn1-positive cells was also observed in the dermal layer of post-wounded skin, the signal that co-localized with Snail1, a transcription factor involved in the epithelial-mesenchymal transition process (EMT; [70]) and Mmp9 (marker of the EMT) [43]. The participation of Foxn1-expressing cells in the EMT process, which leads to scar formation, was further confirmed with a flow cytometry assay, indicating an increase in N-cadherin (a marker of mesenchymal cell characteristics) and E-cadherin + N-cadherin-positive cells within the Foxn1-eGFP isolated cell population at post-wounded day 7 [44]. The presence of Foxn1-eGFP cells was also detected in post-wounded dermis (papillary dermis) during the remodeling phase of skin wound healing [44]. Foxn1-eGFP positive cells presented in the papillary dermis colocalized with \(\alpha\) smooth muscle actin (\(\alpha\)SMA) the myofibroblast marker [44]. Collectively, the data implicate Foxn1 as a transcription activator contributing to the activation of keratins (i.e., keratin16) required for epithelial resurfacing of post-wounded skin tissues and as a factor stimulating the EMT process, which leads to scar formation [43]. Little is known about how Foxn1 is controlled in the skin, including its regulation during the skin wound healing process.