# Foxn1 Control of Skin Function
## 3 Foxn1 Regulates Epidermis and Hair Follicle Physiology  
[PERSON] et al., were the first to investigate Foxn1 function in the skin [32; 37; 41]. A developmental study using transgenic mice in which a \(\beta\)-galactosidase reporter gene was placed under the control of the wild-type Foxn1 promoter revealed Foxn1 expression in epithelial cells of skin, thymus, nails, nasal passages, tongue, palate, and teeth [32]. Whole mounts of heterozygous (whn-lacZ fusion; whn+/-) embryos stained for \(\beta\)-galactosidase activity showed staining (Foxn1 activity) in the developing nasal region at day 13 of gestation, developing mouth, hair follicles of the eyebrows and lashes, and epidermis of the ear and tail at day 14.5. The entire epidermis, including developing hair follicles of the fur coat, expressed \(\beta\)-galactosidase at gestational days E15.5-16.5 [32]. In the epidermis of heterozygous whn-lacZ mice, \(\beta\)-galactosidase activity was predominantly found in the first suprabasal layer, with occasionally observed positive cells in the basal layer of keratinocytes [32]. Location of Foxn1 in the suprabasal layer that contains keratinocytes at the early stage of differentiation suggestedFoxn1 involvement in the process of interfollicular keratinocyte differentiation. Hair follicular whn (Foxn1) expression is primarily associated with the anagen stage (the period of hair growth) when differentiating cells are continuously produced. During hair follicular regression (catagen), Foxn1 expression decreases, becoming undetectable at the telogen (resting) stage [42]. The location of Foxn1-positive cells in the interfollicular suprabasal layer of the epidermis and in hair follicles was further confirmed in Foxn1::EGFP mice (Figure 1), in which the enhanced green fluorescent protein transgene is driven by the Foxn1 regulatory sequence [43; 44]. In a subsequent study, [PERSON] et al., used transgenic mice that express whn (Foxn1) from the promoter of involucrin, which in normal skin is expressed in postmitotic (differentiated) epidermal cells [41]. The results of the study suggest that Foxn1 promotes the differentiation of Foxn1-expressing cells and stimulates the proliferation of neighboring cells through paracrine mechanisms [41; 45]. A study by [PERSON] et al., further confirmed the role of Foxn1 as a transcription factor that activates and stimulates the first stages of keratinocyte differentiation [46]. The overexpression of Foxn1 in cultured keratinocytes stimulated the increase in keratin10-positive cells (marker of differentiated keratinocytes located in the suprabasal layer of epidermis) at the expense of a decrease in the percentage of keratin14-positive cells (marker of proliferative keratinocytes--located in the basal layer of the epidermis) [46]. Recent data have identified Foxn1 as a factor required for skin developmental programs and skin maturation [47]. Detailed comparative analysis of transcriptomes from the skin of adult Foxn1\({}^{+/+}\) and Foxn1\({}^{-/-}\) mice and the skin of mouse fetuses at embryonic day 14 (Foxn1\({}^{-/-}\)) and at embryonic day 18 (Foxn1\({}^{+/+}\)) revealed substantial similarities in the gene expression profiles between E14 and Foxn1\({}^{-/-}\) mice. Genes associated with differentiation and skin development were downregulated in the skin of E14 and Foxn1\({}^{-/-}\) mice, whereas those involved in tissue remodeling, cytoskeletal rearrangements, wound healing, and the immune response showed upregulation [47]. Among the downregulated genes, there were genes encoding transcription factors associated with the homeodomain: Hox genes (_Hoxb3, Hoxb5, Hoxc6_, and _Hoxd13_), extended Hox genes (_Gbx2_), paired domain (_Pax1_), paired-like domain (_Pbx2b_ and _Pitx1_), and six/sine homeobox (_Six1_ and _Six2_). These transcription factors are involved in embryonic development and have been shown to regulate stem cell differentiation [48].