Hairless is a nuclear receptor corepressor that modulates epithelial progenitor cell differentiation

Mutations in the Hairless (Hr) gene were known to cause hair loss in mice and humans. However, the molecular function of the protein encoded by Hr (HR) was not known. Previous analysis showed that HR interacts with thyroid hormone receptor (TR), a nuclear receptor. Here, we demonstrate that HR functions as a corepressor, as HR enhances transcriptional repression by unliganded TR. Additional analysis demonstrates that HR can reduce Vitamin D receptor-dependent reporter gene activity in keratinocytes, a cell type in which HR functions in vivo. Thus, the phenotype of Hr mutant mice, which lack corepressor function, likely results from alterations in gene expression.; Skin is an organ undergoing constant cellular renewal via stem cell-mediated production of progenitors for three subcompartments: epidermis, sebaceous glands, and hair follicles. Subsequent to hair follicle morphogenesis, skin from Hr mutant mice display excess epidermis, then loss of hair follicles and development of cysts that resemble sebaceous glands. This suggested that Hr functions to coordinate epithelial differentiation into three skin lineages by slowing epidermal differentiation and inhibiting sebaceous gland differentiation, while supporting hair follicle differentiation. To test this model, we have generated and analyzed a transgenic mouse overexpressing Hr in progenitor keratinocytes. Consistent with the above model, these Hr transgenic mice display altered hair growth, and delayed epidermal and sebaceous gland differentiation.; To identify the role of HR in hair regrowth, we show HR protein expression is detected in hair follicles during the reinitiation of hair growth. Consistent with the localization of HR, we find that reexpression of Hr in progenitor keratinocytes leads to rescue of hair regrowth in Hr null mice. We identify a Wnt signaling modulator, Wise, which is increased in expression in Hr null mice, and reduced by reexpression of Hr. Additional experiments in vitro and in vivo suggest that Wise expression is repressed by HR through the hair cycle. We propose that by repressing expression of a Wnt inhibitor, HR promotes Wnt signaling, resulting in regeneration of the hair follicle. Together these data show that regulation of gene expression by HR is involved in multiple aspects of epithelial progenitor cell differentiation.