Engelhard Andrew, Christiano Angela M
Department of Dermatology, Columbia University, New York, NY 10032, USA.
Exp Dermatol. 2004 Apr;13(4):257-64. doi: 10.1111/j.0906-6705.2004.00175.x.
The hair cycle is an extraordinarily complex process relying on spatially and temporally coordinated integration of intercellular signaling, cell division and death, cell migration, and gene expression. The hairless gene (hr) is expressed with hair-cycle-dependent kinetics, and pathogenic mutations in hr are responsible for the hairless and rhino phenotypes in mice and atrichia with papular lesions in humans. In addition to its expression in the skin and hair follicle, hr is also highly expressed in the brain, yet the factors governing its differential cell-type-specific expression have not yet been defined. A thyroid hormone responsive element was previously identified in the rat hr promoter which confers thyroid hormone (T3) responsiveness to heterologous promoter constructs; however, prior studies have not focused on the hr promoter itself. The hairless promoter was cloned, and it is shown that the hr promoter is transactivated by T3 in neuroblastoma cells but not in keratinocytes. Therefore, while T3 has a significant role in the regulation of neuronal expression of hairless, its upregulation in keratinocytes is T3 independent. Furthermore, hr is subject to cell-type-specific negative autoregulation, inhibiting the activity of its own promoter in keratinocytes but not neuroblastoma cells. These findings illustrate a molecular distinction between the regulation of hr expression in defined cell populations.
毛发周期是一个极其复杂的过程，依赖于细胞间信号传导、细胞分裂与死亡、细胞迁移以及基因表达在空间和时间上的协调整合。无毛基因（hr）以毛发周期依赖性动力学表达，hr中的致病突变导致小鼠出现无毛和犀牛样表型，以及人类出现伴有丘疹性损害的无毛症。除了在皮肤和毛囊中表达外，hr在大脑中也高度表达，但其在不同细胞类型中特异性表达差异的调控因子尚未明确。先前在大鼠hr启动子中鉴定出一个甲状腺激素反应元件，该元件赋予异源启动子构建体甲状腺激素（T3）反应性；然而，先前的研究并未聚焦于hr启动子本身。克隆了无毛启动子，结果表明hr启动子在神经母细胞瘤细胞中被T3反式激活，但在角质形成细胞中则不然。因此，虽然T3在调节无毛基因的神经元表达中起重要作用，但其在角质形成细胞中的上调与T3无关。此外，hr受到细胞类型特异性的负向自动调节，抑制其自身启动子在角质形成细胞中的活性，但在神经母细胞瘤细胞中则无此作用。这些发现说明了在特定细胞群体中hr表达调控的分子差异。
