Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development

Abstract

SummaryThe process by which the periderm transitions to stratified epidermis with the establishment of the skin barrier is unknown. Understanding the cellular and molecular processes involved is crucial for the treatment of human pathologies, where abnormal skin development and barrier dysfunction are associated with hypothermia and perinatal dehydration. For the first time, we demonstrate that retinoic acid (RA) levels are important for periderm desquamation, embryonic skin differentiation and barrier formation. Although excess exogenous RA has been known to have teratogenic effects, little is known about the consequences of elevated endogenous retinoids in skin during embryogenesis. Absence of cytochrome P450, family 26, subfamily b, polypeptide 1 (Cyp26b1), a retinoic-aciddegrading enzyme, results in aberrant epidermal differentiation and filaggrin expression, defective cornified envelopes and skin barrier formation, in conjunction with peridermal retention. We show that these alterations are RA dependent because administration of exogenous RA in vivo and to organotypic skin cultures phenocopy Cyp26b1 -/-skin abnormalities. Furthermore, utilizing the Flaky tail (Ft/Ft) mice, a mouse model for human ichthyosis, characterized by mutations in the filaggrin gene, we establish that proper differentiation and barrier formation is a prerequisite for periderm sloughing. These results are important in understanding pathologies associated with abnormal embryonic skin development and barrier dysfunction.

Hyperglycemia Induces Skin Barrier Dysfunctions with Impairment of Epidermal Integrity in Non-Wounded Skin of Type 1 Diabetic Mice

“…Lucifer yellow (LY) dye with 0.95 nm in diameter cannot penetrate into the epidermis [21], therefore it was utilized to examine the epidermal barrier functions against external assaults. In particular, the outside-in barrier function in the stratum corneum would be an important target to evaluate [15, 22]; therefore, the recently developed in vivo dye penetration assay [14] was used in this study. Consistent with previous studies [15, 22], we found that positive signals were confined to hair follicles and to the outer surface of the stratum corneum in the control mice (Fig 2A).…”

“…In particular, the outside-in barrier function in the stratum corneum would be an important target to evaluate [15, 22]; therefore, the recently developed in vivo dye penetration assay [14] was used in this study. Consistent with previous studies [15, 22], we found that positive signals were confined to hair follicles and to the outer surface of the stratum corneum in the control mice (Fig 2A). By contrast, LY signals were sporadically observed in the stratum corneum of the diabetic mice (Fig 2A).…”

“…CEs were prepared from 20 mm x 25 mm of ventral skin as previously described [15]. Briefly, CEs were isolated by boiling the extraction buffer (2% SDS, 100 mM Tris-HCl pH8.0, 5 mM EDTA, 20 mM DTT, followed by 0.2% SDS, 100 mM Tris-HCl pH8.0, 5 mM EDTA, 20 mM DTT) and by centrifuging (12, 000 x G) between each step, followed by resuspension in 1 ml of 100 mM Tris/EDTA.…”

Retinoic Acid-Induced Epidermal Transdifferentiation in Skin

“…ATRA induces a catagen-like stage in human hair follicles, presumably via up-regulation of TGF-β2 in the dermal papilla, resulting in hair loss [62]. In a mouse model which knocked out cytochrome P450, family 26, subfamily b, polypeptide 1 (Cyp26b1), which encodes an RA-degrading enzyme, the in vivo administration of RA to pregnant mice or its addition to skin cultures demonstrated that appropriate RA levels are important for periderm desquamation, embryonic skin differentiation, and barrier formation in the developing mammalian skin [26]. Furthermore knock-out mouse lacking Cyp26b1 in their skin exhibit major hair follicle development defects [27].…”

“…Interestingly, ATRA-induced expression of Tgm2 (transglutaminase 2) and Gbx1 in the epidermis and that of TGF-β2 expression in the dermis are required for the mucosal transdifferentiation [22]. Other than the transdifferentiation, RA also plays an important role in barrier formation and hair follicle formation in skin [6,7,[23][24][25][26][27]. This review highlights our current understanding of the role of retinoic acid in the epidermal transdifferentiation of skin and its appendages.…”