Development of an Ichthyosiform Phenotype in Alox12b-Deficient Mouse Skin Transplants
Development of an Ichthyosiform Phenotype in Alox12b-Deficient Mouse Skin Transplants
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DOI：
10.1038/jid.2008.410
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发表时间：
2009-06-01
影响因子：
6.5
通讯作者：
Krieg, Peter
中科院分区：
文献类型：
--
作者：
de Juanes, Silvia;Epp, Nikolas;Krieg, Peter
12r -脂氧合酶（12R-LOX）是最近发现的皮肤类二十烷途径的关键酶，在表皮屏障功能的建立和/或维持中起重要作用。遗传学研究表明，编码12R-LOX的ALOX12B基因和编码另一密切相关的LOX基因的ALOXE3基因的功能缺失突变是常染色体隐性遗传先天性鱼鳞病（ARCI）的第二大常见原因。为了研究ARCI的发病机制和12R-LOX的功能，我们最近建立了一个12R-LOX敲除模型。12r - lox缺陷小鼠在出生后很快死于严重的屏障功能障碍，没有明显的皮肤表型。因此，我们分析了移植到裸鼠身上的12R-LOX-/-皮肤的成年表型。12R-LOX-/-皮肤呈现鱼鳞样外观，伴有表皮增厚、增生、颗粒过多、局灶性角化不全和严重角化过度。成年突变小鼠的皮肤表型与ALOX12B突变患者的鱼鳞病表型密切相关。Western blot分析显示，过去在新生儿突变皮肤中受到干扰的聚丝蛋白加工恢复，聚丝蛋白、天青蛋白和重复蛋白过度表达。结果表明，12R-LOX敲除小鼠可能是一种有用的动物模型，可用于详细分析与LOX代谢受损相关的ARCI形式的机制。Journal of Investigative Dermatology (2009) 129, 1429-1436；doi: 10.1038 / jid.2008.410;2009年1月1日在网上发布
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. Journal of Investigative Dermatology (2009) 129, 1429-1436; doi:10.1038/jid.2008.410; published online 1 January 2009