P1.1 Foxn1 is Critical for Onychocyte Terminal Differentiation in Nude (Foxn1^nu) Mice

Lars Mecklenburg,^1,3 Ralf Paus,¹ Zdenek Halata,² Lesley S. Bechtold,⁴ Philip Fleckman,⁵ and John P. Sundberg⁴

¹Departments of Dermatology and ²Anatomy, University Hospital Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany; ³Veterinary Dermatopathology Consultant, Hamburg, Germany; ⁴The Jackson Laboratory, Bar Harbor, Maine, USA; and ⁵Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA, USA.

Objective: Nude mice have a mutation in the transcription factor Foxn1^nu, resulting in down regulation of hair keratins. Although hair follicles develop normally, hair fibers become structurally weak, curl, and break off at the surface, resulting in alopecia. Our objective was to determine if nails in these mutant mice are also deformed.

Methods: Normal and mutant nude mice were studied on two inbred backgrounds by histology, immunohistochemistry, scanning and transmission electron microscopy, and elemental analysis with comparison to the hair.

Results: Nude mice develop severe onychodystrophy, based on alterations of the onychocyte differentiation process within the nail matrix. 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 towards an epidermis-like differentiation pattern, comprising the production of filaggrin-containing keratohyalin granules immediately below the nail plate, 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.

Conclusions: These studies indicate that Foxn1^nu has effects beyond down-regulating keratins, including changes in filaggrin expression, and is critical for normal onychocyte terminal 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.