Targeted ablation of Arnt in mouse epidermis results in profound defects in desquamation and epidermal barrier function

Abstract

The molecular mechanisms of skin adaptation to the environmental stress are poorly understood. The aryl hydrocarbon receptor nuclear translocator (Arnt) lies at the intersection of several crucial adaptive pathways. Nevertheless, its role in adaptation of the skin to environmental stress has just begun to be unraveled. Here we show that Arnt is expressed in human and mouse skin in a developmentally dependent manner. Targeted K14-driven deletion of Arnt in the mouse epidermis resulted in early postnatal death, associated with a failure of epidermal barrier function. Gene expression profiling of Arnt-null mouse epidermis revealed upregulation of genes of the epidermal differentiation complex on mouse chromosome 3, including S100a genes (S100a8, S100a9, S100a10) and genes coding for small proline-rich proteins (Sprr1a, Sprr2i, Sprr2j, Sprrl1). HPTLC analysis showed significant accumulation of Cer[NS] and Cer[NH] ceramide species in Arnt-null epidermis, suggesting alterations in lipid metabolism. Continuous retention of corneosomes in Arnt-null epidermis that resulted in an abnormally dense corny layer and impaired desquamation was associated with upregulation of Slpi, an inhibitor of stratum corneum chymotryptic enzyme (SCCE) that plays a key role in corneosome degradation. The functional defects in Arnt-null mouse epidermis underscore the crucial role of Arnt in the maintenance of epidermal homeostasis, especially during the perinatal transition to the ex utero environment.

EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes

“…Two independent studies have shown that targeted ablation of Arnt in the mouse epidermis results in early postnatal death associated with a failure of epidermal permeability barrier function (18,19). In each study, histology showed small changes in the architecture of the cornified layers.…”

“…In each study, histology showed small changes in the architecture of the cornified layers. Biochemical analyses revealed changes in lipid metabolism affecting permeability, specifically alterations of the 4-sphingenine scaffolds of ceramides (18), and ceramide metabolism, including downregulation of the UGCG pathway in the Arnt null epidermis (19). In one study, microarray analysis revealed that the expression of FLG was regulated by ARNT (19).…”

“…Biochemical analyses revealed changes in lipid metabolism affecting permeability, specifically alterations of the 4-sphingenine scaffolds of ceramides (18), and ceramide metabolism, including downregulation of the UGCG pathway in the Arnt null epidermis (19). In one study, microarray analysis revealed that the expression of FLG was regulated by ARNT (19). Because ARNT is the heterodimer partner of the AHR, and the expression of FLG was elevated by TCDD treatment of NHEKs, we examined the expression of 2 additional genes critical to sphingolipid and ceramide biosynthesis in skin and regulated by Arnt (19,20).…”

“…In one study, microarray analysis revealed that the expression of FLG was regulated by ARNT (19). Because ARNT is the heterodimer partner of the AHR, and the expression of FLG was elevated by TCDD treatment of NHEKs, we examined the expression of 2 additional genes critical to sphingolipid and ceramide biosynthesis in skin and regulated by Arnt (19,20). This work showed that the expression of UCGC and DEGS2 (DES2) was increased by TCDD treatment and repressed by EGF.…”

“…4 E-G). These genes included filaggrin (FLG), ceramide glucosyltransferase (UGCG), and sphingolipid C4-hydroxylase/ delta 4-desaturase (DEGS2), all known to be regulated by ARNT during cornification (late differentiation) and to contribute to epidermal barrier function (18,19). Also, treatment with EGF markedly inhibited both the cell density-dependent and TCDDmediated expression of each of these 3 genes (Fig.…”