Identification of novel glucocorticoid receptor-regulated genes involved in epidermal homeostasis and hair follicle differentiation

Abstract

Despite that glucocorticoids (GCs), acting through the glucocorticoid receptor (GR) exert a pivotal role in skin physiopathology, specific genes regulated by GR in this tissue are largely unknown. We have used a transgenic mouse model overexpressing GR in epidermal basal cells and outer root sheath (ORS) of the hair follicle (HF) under the control of the keratin 5 regulatory sequences (K5-GR mice) to identify GR-regulated genes in mouse skin. We analyzed the transcriptomic profile of adult K5-GR skin as compared to non-transgenic adult mice by using oligonucleotide microarrays and identified 173 genes differentially regulated by GR in this tissue. Our data were further validated by semiquantitative RT-PCR and quantitative real-time PCR. We have identified a large subset of hair keratin intermediate filament (krt) and hair keratin-associated protein (krtap) genes, as well as several hox genes as GC-regulated. Since dysregulation of krt, krtaps and hox genes can cause hair disorders, as it occurs in adult K5-GR mice, our findings strongly suggest a role of GR in HF morphogenesis through the coordinated regulation of these hair-specific genes. In addition, we found that GR repressed several genes related to cell growth, such as the immediate early genes fosb and c-fos, according to the antiproliferative role described for this hormone receptor. By using cultured keratinocytes treated with GR-agonists and -antagonists, we demonstrated that down-regulation of fosb is mediated by GR. Identification of novel GR-regulated genes will help us to better understand the role of GCs as physiological modulators and pharmacological agents.