FOXN1 Is Critical for Onycholemmal Terminal Differentiation in Nude (Foxn1nu) Mice

Abstract

Nude mice have a mutation in the transcription factor Foxn1(nu), resulting in downregulation of hair keratins. Although hair follicles develop normally, the hair fibers become structurally weak, curl, and break off at the surface. Nails in nude mice are deformed, based on alterations of the onychocyte differentiation process. Elemental microanalysis of the nail plate reveals marked decreases in sulfur concentrations in the nude mouse nail plates. Immunohistochemistry shows a lack of keratin 1 expression in terminally differentiating keratinocytes of the nail matrix. Instead, the typical differentiation process of the matrix is altered toward an epidermis-like differentiation pattern, comprising the production of filaggrin-containing keratohyalin granules in cells resembling those of the stratum granulosum, which are never observed in normally haired mice. The nail plate has diffuse basophilic stippling. It is thinner than normal, weak, and in most Foxn1(nu)/Foxn1(nu) mice breaks where it separates from the hyponychium. These studies indicate that the Foxn1(nu) mutated gene has effects beyond downregulating keratin expression, including changes in filaggrin expression, and is critical for normal onycholemmal differentiation. The nails of nude mice provide new insights into the molecular controls of onychocyte differentiation, and they offer a useful model to investigate the pathogenesis of nail hypergranulosis, a common feature in human nail diseases.

Developmental expression of chicken FOXN1 and putative target genes during feather development

“…Alpha keratins are found in the feather sheath and barb ridges but are rapidly overwhelmed by deposition of beta keratins (Alibardi, 2013). Since one function of transcription factor FOXN1 in mice is the activation of alpha keratins 2-6 (Schlake et al, 2000;Mecklenburg et al, 2004) and birds appear primarily to use beta keratin proteins in feathers, it has not been tested whether feathers express FOXN1. We previously showed that another Forkhead transcription factor, FOXE1, is transcribed in the feather filament (Yaklichkin et al, 2011), and its mammalian ortholog is implicated in hair morphogenesis (Brancaccio et al, 2004).…”

“…In addition to regulating keratins (e.g., Mecklenburg et al, 2004), the regulation of MHC Class II genes, BRD2 (Bromodomain-containing gene 2), CTSL (Cathepsin L, a lysosomal protease), CD40 (TNF-related receptor), and DLL4 (delta-like gene 4) was positively correlated with FOXN1 dosage (Nowell et al, 2011;hESnet). To determine if these components represent a gene regulatory network that is conserved in other FOXN1-expressing tissues, we used in situ hybridization to evaluate the expression of chick homologs of these genes in feathers and other epidermal appendages.…”

“…hair is due to a coiling of hair shafts in the hair canal resulting in a failure to penetrate the epidermal layer of the skin or breaking off at the surface (Mecklenburg et al, 2001(Mecklenburg et al, , 2004(Mecklenburg et al, , 2005. Similarly, humans with FOXN1 mutation have congenital alopecia (hair loss), nail dystrophy and immunodeficiency (Frank et al, 1999, Pignata et al, 2009.…”

Skin Diseases in Laboratory Mice: Approaches to Drug Target Identification and Efficacy Screening

“…A concurrent qualitative or semi-quantitative follow up can be done, when the SEM is appropriately equipped to perform element analysis on the hair shafts. Sulfur levels are higher in hair shafts and nails than epidermis of the skin due to the presence of the hard (hair and nail) keratins and keratin associated proteins which are often proteins containing high to ultrahigh sulfur containing amino acids [102]. Hair defects are often due to low sulfur levels, e.g.…”

“…Samples should be examined for an average of at least 300 live seconds to ensure a comprehensive reading is obtained [102].…”