Ectopic expression of the nude gene induces hyperproliferation and defectsin differentiation: Implications for the self-renewal of cutaneous epithelia

Nude mice are characterized by the absence of visible hair, epidermal defec ts, and the failure to develop a thymus. This phenotype results from loss-o f-function mutations in Whn (Hfh11), a winged-helix transcription factor. I n murine epidermis and hair follicles, endogenous whn expression is induced as epithelial cells initiate terminal differentiation. Using the promoter for the differentiation marker involucrin, transgenic mice that ectopically express whn in stratified squamous epithelia, hair follicles, and the tran sitional epithelium of the urinary tract were generated. Transgenic epiderm is and hair follicles displayed impaired terminal differentiation and a sub set of hair defects, such as delayed growth, a waved coat, and curly whiske rs, correlated with decreased transforming growth factor (TGF)-alpha expres sion. The exogenous Whn protein also stimulated epithelial cell multiplicat ion. In the epidermis, basal keratinocytes exhibited hyperproliferation, th ough transgene expression was restricted to suprabasal, postmitotic cells. Hair follicles failed to enter telogen (a resting period) and remained cont inuously in an abnormal anagen (the growth phase of the hair cycle). Ureter epithelium developed severe hyperplasia, leading to the obstruction of uri ne outflow and death from hydronephrosis. Though an immune infiltrate was p resent occasionally in transgenic skin, the infiltrate was not the primary cause of the epithelial hyperproliferation, as the immune reaction was not observed in all affected transgenics, and the transgene induced identical s kin and urinary tract abnormalities in immunodeficient Rag1-null mice. Give n the effects of the transgene on cell proliferation and TGF alpha expressi on, the results suggest that Whn modulates growth factor production by diff erentiating epithelial cells, thereby regulating the balance between prolif erative and postmitotic populations in self-renewing epithelia. (C) 1999 Ac ademic Press.