Identification of novel glucocorticoid receptor-regulated genes involved in epidermal homeostasis and hair follicle differentiation.
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.
Donet
Eva
E
Centro de Investigación Príncipe Felipe CIPF, Avenida Autopista del Saler 16, Camino de las Moreras, Valencia, Spain.
Bayo
Pilar
P
Calvo
Ezequiel
E
Labrie
Fernand
F
Pérez
Paloma
P
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018859:Hair Follicle / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011965:Receptors, Glucocorticoid / Q000502:physiology*
D011965:Receptors, Glucocorticoid