Development of an Ichthyosiform Phenotype in Alox12b-Deficient Mouse Skin Transplants

Abstract

12R-lipoxygenase (12R-LOX) represents a key enzyme of a recently identified eicosanoid pathway in the skin that plays an essential role in the establishment and/or maintenance of the epidermal barrier function. Genetic studies show that loss-of-function mutations in ALOX12B, encoding 12R-LOX, and in ALOXE3, encoding another closely related LOX involved in this pathway, are the second most common cause for autosomal recessive congenital ichthyosis (ARCI). To investigate the pathomechanism of ARCI and the function of 12R-LOX, we recently generated a 12R-LOX knockout model. 12R-LOX-deficient mice die rapidly after birth from severe barrier dysfunction without exhibiting an obvious cutaneous phenotype. Thus, we analyzed the adult phenotype of 12R-LOX(-/-) skin transplanted onto nude mice. 12R-LOX(-/-) skin develops an ichthyosiform appearance with thickening of the epidermis, hyperproliferation, hypergranulosis, focal parakeratosis, and severe hyperkeratosis. The adult mutant mouse skin phenotype closely reproduces the ichthyosis phenotype seen in patients with ALOX12B mutations. Western blot analysis revealed restoration of profilaggrin processing that used to be disturbed in neonatal mutant skin and overexpression of filaggrin, involucrin, and repetin. The results indicate that 12R-LOX knockout mice may represent a useful animal model for a detailed analysis of mechanisms involved in ARCI forms that are associated with impaired LOX metabolism.

Cytochrome b 5 null mouse: a new model for studying inherited skin disorders and the role of unsaturated fatty acids in normal homeostasis

“…1i). Similar increases in epidermal thickness and keratinization have been reported on disruption of the 12R-lipoxygenase, ALOX12B locus, in mice, an enzyme involved in an alternative pathway of arachidonic acid metabolism in the skin, and suggests that cytochrome b 5 may also contribute to this pathway of eicosanoid biosynthesis (Juanes et al 2009). The skin phenotypes observed in BCN mice are highly similar to those observed in the human diseases classed as autosomal recessive congenital ichthyosis (ARCI) (Akiyama and Shimizu 2008).…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…The neonatal Alox12b (e/e) mouse phenotype presented with thin, highly inflamed skin leading to dehydration and death within several hours (genetically impaired SC barrier), but the transplanted rescued adult phenotype of the lipoxygenase-deficient skin developed a mouse ichthyosis with severe hyperkeratosis (homeostatic response). 173 Such functional models correlate with the phenotypic shift in EI (or HI), where differences in barrier requirements between the wet intrauterine versus the dry postnatal environments produce strikingly different phenotypes at birth versus thereafter.…”

Self-Improvement of Keratinocyte Differentiation Defects During Skin Maturation in ABCA12-Deficient Harlequin Ichthyosis Model Mice

“…18 Mature 12R-lipoxygenase knockout mouse skin showed recovery of skin barrier function and restoration of profilaggrin conversion after maturation, which had been lacking in the neonatal mice. 19,20 In addition, mature transglutaminase 1 knockout mouse skin also showed skin barrier functional recovery, although exact compensation mechanisms other than hyperkeratosis were not identified. 21 To find any clues for the mechanism of compensation in Abca12 Ϫ/Ϫ mice, we conducted cDNA microarray analysis.…”