To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease
To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease
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DOI：
10.1016/j.ajpath.2015.12.030
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发表时间：
2016-05-01
影响因子：
6
通讯作者：
Garza, Luis A.
中科院分区：
文献类型：
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作者：
Kim, Dongwon;Hossain, M. Zulfiquer;Garza, Luis A.
尽管成分相似，但人体皮肤特征的异质性是巨大的。传统上认为，真皮中的位点特异性成纤维细胞通过调节表皮中表面覆盖的角质形成细胞的行为来控制出生后的皮肤特性。为了开始测试这一假设，我们描述了掌侧（腹侧;掌跖）和非掌侧（背侧）人类皮肤之间的基因表达差异。我们发现角蛋白9（KRT 9）是掌侧皮肤中最独特的富集转录物，与其在手掌和足底遗传疾病中的病因学一致。此外，异位KRT 9表达被掌侧成纤维细胞选择性激活。然而，KRT 9表达在所有成纤维细胞不存在的情况下发生，尽管未达到成纤维细胞诱导的最大水平。通过功能获得和功能丧失的实验，我们证明了其机制是通过重叠的旁分泌或自分泌经典WNT-β-连环蛋白信号在各自的情况下。最后，作为独立于掌侧成纤维细胞的KRT 9异位表达的体内实例，我们证明了在人类皮肤病慢性单纯性苔藓中，WNT 5a和KRT 9在掌侧位点之外被稳健地激活。这些结果突出了皮肤病中位点特异性基因表达及其破坏的复杂性。
Despite similar components, the heterogeneity of skin characteristics across the human body is enormous. It is classically believed that site-specific fibroblasts in the dermis control postnatal skin identity by modulating the behavior of the surface-overlying keratinocytes in the epidermis. To begin testing this hypothesis, we characterized the gene expression differences between volar (ventral; palmoplantar) and nonvolar (dorsal) human skin. We show that KERATIN 9 (KRT9) is the most uniquely enriched transcript in volar skin, consistent with its etiology in genetic diseases of the palms and soles. In addition, ectopic KRT9 expression is selectively activated by volar fibroblasts. However, KRT9 expression occurs in the absence of all fibroblasts, although not to the maximal levels induced by fibroblasts. Through gain-of-function and loss-of-function experiments, we demonstrate that the mechanism is through overlapping paracrine or autocrine canonical WNT-beta-catenin signaling in each respective context. Finally, as an in vivo example of ectopic expression of KRT9 independent of volar fibroblasts, we demonstrate that in the human skin disease Lichen simplex chronicus, WNT5a and KRT9 are robustly activated outside of volar sites. These results highlight the complexities of site-specific gene expression and its disruption in skin disease.