12R-lipoxygenase (12R-LOX) and the epidermal LOX-3 (eLOX-3) constitute a novel LOX pathway involved in terminal differentiation in skin. This view is supported by recent studies showing that inactivating mutations in 12R-LOX and eLOX-3 are linked to the development of autosomal recessive congenital ichthyosis. We show that 12R-LOX deficiency in mice results in a severe impairment of skin barrier function. Loss of barrier function occurs without alterations in proliferation and stratified organization of the keratinocytes, but is associated with ultrastructural anomalies in the upper granular layer, suggesting perturbance of the assembly/extrusion of lamellar bodies. Cornified envelopes from skin of 12R-LOX–deficient mice show increased fragility. Lipid analysis demonstrates a disordered composition of ceramides, in particular a decrease of ester-bound ceramide species. Moreover, processing of profilaggrin to monomeric filaggrin is impaired.This study indicates that the 12R-LOX–eLOX-3 pathway plays a key role in the process of epidermal barrier acquisition by affecting lipid metabolism, as well as protein processing.

is the interaction with its receptor expressed at the cell surface. Reverse transcription polymerase chain reaction (RT-PCR)A PGF 2α (FP)-specific receptor has recently been cloned from and Northern blot analysis was used to determine the level cDNA libraries originating from different species, including of expression of prostaglandin F 2α (FP) receptor mRNA in mouse (7). In this paper, we have analyzed the expression of various mouse tissues, including normal, hyperplastic and this FP receptor in normal, hyperplastic and neoplastic mouse neoplastic mouse epidermis. Steady-state concentrations of epidermis, as well as in various other mouse tissues. FP receptor mRNA were low in normal and hyperplasticSeven-week-old female NMRI mice (BRL, Füllinsdorf, epidermis. The response of the epidermis to the phorbol Switzerland) were used in the animal experiments. Shaving of ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was the back skin with electrical clippers was performed 3 days biphasic in that FP receptor mRNA was increased immediprior to treatment. For topical applications, compounds were ately after treatment, followed by a long-lasting downdissolved in 0.1 ml acetone and applied onto the shaved back regulation at later time points. FP receptor mRNA was skin. Mice were killed at varying time-points, the back skin down-regulated in the majority of papillomas obtained was dissected and snap-frozen at -70°C using a cold table. by the mouse skin carcinogenesis initiation-promotionMouse skin tumors were generated by the mouse skin carcinoprotocol. In carcinomas, FP receptor mRNA expression genesis initiation-promotion protocol using DMBA (100 nmol/ was similar to that in normal epidermis. The steady-state 0.1 ml acetone; single epicutaneous application) and TPA (10 concentration of FP mRNA was inversely correlated with nmol/0.1 ml acetone; twice-weekly applications for 20 weeks). PGF 2α levels in normal and hyperplastic epidermis and in Papillomas were harvested 22 weeks after initiation, i.e. papillomas, indicating that FP mRNA expression is regu-2 weeks after the last TPA treatment, and carcinomas 40 weeks lated by this eicosanoid.after initiation, i.e. 20 weeks after the last TPA treatment. Great care was taken during the preparation of tumors to avoid contamination by non-epithelial material.

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