Learning from nudity: lessons from the nude phenotype

Abstract

In mice, rats, and humans, loss of function of Foxn1, a member of the winged helix/forkhead family of transcription factors, leads to macroscopic nudity and an inborn dysgenesis of the thymus. Nude (Foxn1 nu /Foxn1 nu ) mice develop largely normal hair follicles and produce hair shafts. However, presumably because of a lack of certain hair keratins, the hair shafts that are generated twist and coil in the hair follicle infundibulum, which becomes dilated. Since hair shafts fail to penetrate the epidermis, macroscopic nudity results and generates thegrossly misleading -impression that nude mice are hairless. Here, we provide an overview of what is known on the role of Foxn1 in mammalian skin biology, its expression patterns in the hair follicle, its influence on hair follicle function, and onychocyte differentiation. We focus on the mechanisms and signaling pathways by which Foxn1 modulates keratinocyte differentiation in the hair follicle and nail apparatus and summarize the current knowledge on the molecular and functional consequences of a loss of function of the Foxn1 protein in skin. Foxn1 target genes, gene regulation of Foxn, and pharmacological manipulation of the nude phenotype (e.g. by cyclosporine A, KGF, and vitamin D3) are discussed, and important open questions as well as promising research strategies in Foxn1 biology are defined. Taken together, this review aims at delineating why enhanced research efforts in this comparatively neglected field of investigative dermatology promise important new insights into the controls of epithelial differentiation in mammalian skin.

Control of hair follicle cell fate by underlying mesenchyme through a CSL–Wnt5a–FoxN1 regulatory axis

“…Hair follicle morphogenesis and cycling are critically dependent on an interplay between keratinocytes and cues originating from the underlying mesenchyme (Botchkarev and Paus 2003). Several key developmental pathways are involved in establishing and/or maintaining the hair follicle keratinocyte cell fate, in concert with keratinocyte-specific genes like FoxN1, a transcription factor whose mutation results in the nude (mouse, rat, or human) phenotype (Mecklenburg et al 2005).…”

A function for Rac1 in the terminal differentiation and pigmentation of hair

“…The transcriptional repressor CCAAT displacement protein (CDP) is required for the formation of a normal inner root sheath (IRS) (Ellis et al, 2001). The transcription factor Foxn1 is essential for hair differentiation and hair shaft formation as well as hair pigmentation (Mecklenburg, 2001;Mecklenburg et al, 2005;Weiner et al, 2007). The wnt signaling pathway involving bcatenin and Lef1 is another important pathway regulating hair formation (Niemann and Watt, 2002).…”

Lectin-like Receptor Ly49s3 on Dendritic Cells Contributes to the Differentiation of Regulatory T Cells in the Rat Thymus

“…Well-known examples of hairless animals, the nude mouse and rat, are also characterized by an abnormal immune system devoid of T cells owing to a deficiency in thymic development (14,15). In these animals, mutations in the Foxn1 gene are responsible for both the immunodeficiency and the hairless phenotype because Foxn1 is a critical transcription factor for the differentiation and survival of both thymic and skin epithelial cells (14,15). In HHRs, we demonstrated a deletion of 80 kb of genomic DNA containing five basic keratin genes as the reason for the hairless phenotype (16).…”

“…In our laboratory, we maintain a mutant strain of rats, the Hirosaki hairless rat (HHR), which was spontaneously derived from the Sprague-Dawley rat (SDR) in 1985, with a nearly bare phenotype that is inherited in an autosomal recessive manner (13). Well-known examples of hairless animals, the nude mouse and rat, are also characterized by an abnormal immune system devoid of T cells owing to a deficiency in thymic development (14,15). In these animals, mutations in the Foxn1 gene are responsible for both the immunodeficiency and the hairless phenotype because Foxn1 is a critical transcription factor for the differentiation and survival of both thymic and skin epithelial cells (14,15).…”