The co-repressor hairless has a role in epithelial cell differentiation in the skin

Although mutations in the mammalian hairless (Hr) gene result in congenital hair loss disorders in both mice and humans, the precise role of Hr in skin biology remains unknown. We have shown that the protein encoded by Hr (HR) functions as a nuclear receptor co-repressor. To address the role of HR in vivo, we generated a loss-of-function (Hr^-/-) mouse model. The Hr^-/- phenotype includes both hair loss and severe wrinkling of the skin. Wrinkling is correlated with increased cell proliferation in the epidermis and the presence of dermal cysts. In addition, a normally undifferentiated region, the infundibulum, is transformed into a morphologically distinct structure (utricle) that maintains epidermal function. Analysis of gene expression revealed upregulation of keratinocyte terminal differentiation markers and a novel caspase in Hr^-/- skin, substantiating HR action as a co-repressor in vivo. Differences in gene expression occur prior to morphological changes in vivo, as well as in cultured keratinocytes, indicating that aberrant transcriptional regulation contributes to the Hr^-/- phenotype. The properties of the cell types present in Hr^-/- skin suggest that the normal balance of cell proliferation and differentiation is disrupted, supporting a model in which HR regulates the timing of epithelial cell differentiation in both the epidermis and hair follicle.