Association between MousenudeGene Expression and the Initiation of Epithelial Terminal Differentiation

Abstract

Loss-of-function mutations in Whn (Hfh 11), a winged-helix/forkhead transcription factor, result in the nude mouse phenotype. To determine thewhnexpression pattern during development, we utilized mice in which a β-galactosidase reporter gene was placed under the control of the wild-typewhnpromoter by homologous recombination (M. Nehlset al.,1996,Science272, 886–889). Sites of reporter expression were confirmed by immunohistochemical staining for Whn protein or byin situhybridization forwhnmRNA. At all developmental stages,whnexpression is restricted to epithelial cells. In addition to the skin and thymus,whnis expressed in the developing nails, nasal passages, tongue, palate, and teeth. In embryonic epidermis, suprabasal cells inducewhnexpression at the same time that terminal differentiation markers first appear. As the epidermis matures,whnpromoter activity is found primarily in the first suprabasal layer, which contains keratinocytes in the early stages of terminal differentiation. In developing and mature anagen hair follicles,whnis expressed at high levels in the postmitotic precursor cells of the hair shaft and inner root sheath. Though principally associated with terminal differentiation,whnexpression is also detected in progenitor cell compartments; in the hair bulb matrix and basal epidermal layer, a small subclass of cells expresseswhn,while in the outer root sheath,whnpromoter activity is induced as the follicle completes its elongation. Within these compartments, rare cells exhibit bothwhnexpression and the nuclear proliferation marker Ki-67. The results suggest thatwhnexpression encompasses the transition from a proliferative to a postmitotic state and thatwhnregulates the initiation of terminal differentiation.