# Foxn1 Control of Skin Function
## 2 Foxn1 Discovery, Structure, and Localization  
Foxn1 belongs to the superclass Helix-turn-helix, class Fork head/winged helix of transcription factors. Named after the Drosophila melanogaster gene fork head (fkh), this family of transcriptional regulators received the name Forkhead box (Fox) [20].  
There are 44 (mouse) and 50 (human) members of the Fox family that are divided into 19 subfamilies, from A to S. The common feature of Fox proteins is the highly conserved \(\sim\)100-residue fork head DNA-binding domain [21]. The Fox gene family is an ancient class of transcription factors with broad functions in development, physiology, and pathology (i.e., cancer) [20]. Most Fox transcription factors act as transcriptional activators, although some (i.e., the FoxP family) has dual activator/suppressor functions [22]. The Foxn group consists of transcription factors named from 1 to 4.  
The mapping and sequencing of the transcription factor Foxn1 in 1994, was preceded 30 years earlier by the spontaneous appearance of phenotypically (hairless) nude mice in an albino stock at the Virus Laboratory, Ruchill Hospital, Glasgow, (UK) [23; 24]. The mice were characterized by a lack of visible hair and a lack of thymus, resulting in T-cell deficiency. Because of their immunodeficiency, nude mice rapidly became the ideal host for xenograft studies investigating predominantly human cancerous tumors. In 1994, [PERSON] et al. showed that a single-base-pair (G) deletion in exon 3 of the whn gene (the former name of Foxn1) causes a frameshift resulting in aberrant protein that lack the DNA-binding domain [25]. The results of the study provided strong evidence that the nude mouse phenotype is the result of the mutation in the Foxn1 (whn) gene. Further study revealed the presence of a nude phenotype due to a Foxn1 mutation in humans [26; 27] and rats [25; 28]. In mice, Foxn1 is located on chromosome 11, and in humans, it is located on chromosome 17. In humans and mice, the Foxn1 gene consists of eight coding exons with two alternative first exons: 1a and 1b. Interestingly, a study by [PERSON] et al., revealed tissue-specific alternative first exon usage [29]. While 1a-2 transcripts were detected in mouse thymus and skin, transcript 1b-2 was detected only in the skin. The authors concluded that these results indicate the presence of two separate promotors: one upstream of exon 1a and the second upstream of exon 1b [29].  
The predicted protein product of the Foxn1 gene consists of 648 amino acids with 85% homology between humans and mice [29]. Tissue-specific Foxn1 expression is located in the epithelium of the thymus and the skin, and recessive nude alleles lead to abnormalities in cutaneous and thymic epithelial development (nude phenotype) [24; 30; 31]. The skin of nude mice contains the same number and normally cycling hair follicles as wild-type mice, but the defect in keratinization of the hair shaft makes them non-growing above the skin surface and causes impairment in the nail matrix [32]. In the thymus, Foxn1 is expressed in thymic epithelial cells (TECs), in which it is involved in thymus development and TEC differentiation [33]. The expression and functional study of Foxn1 in the thymus was meticulously conducted by several groups of investigators [34; 35; 36; 33]. Foxn1 in the skin has attracted less attention; however, comprehensive experiments consistently show the importance of Foxn1 in skin physiology [37; 38; 39; 40].