Zarach Joanna M, Beaudoin Gerard M J, Coulombe Pierre A, Thompson Catherine C
Kennedy Krieger Research Institute, Baltimore, MD 21205, USA.
Development. 2004 Sep;131(17):4189-200. doi: 10.1242/dev.01303. Epub 2004 Jul 27.
Although mutations in the mammalian hairless (Hr) gene result in congenital hair loss disorders in both mice and humans, the precise role of Hr in skin biology remains unknown. We have shown that the protein encoded by Hr (HR) functions as a nuclear receptor co-repressor. To address the role of HR in vivo, we generated a loss-of-function (Hr-/-) mouse model. The Hr-/- phenotype includes both hair loss and severe wrinkling of the skin. Wrinkling is correlated with increased cell proliferation in the epidermis and the presence of dermal cysts. In addition, a normally undifferentiated region, the infundibulum, is transformed into a morphologically distinct structure (utricle) that maintains epidermal function. Analysis of gene expression revealed upregulation of keratinocyte terminal differentiation markers and a novel caspase in Hr-/- skin, substantiating HR action as a co-repressor in vivo. Differences in gene expression occur prior to morphological changes in vivo, as well as in cultured keratinocytes, indicating that aberrant transcriptional regulation contributes to the Hr-/- phenotype. The properties of the cell types present in Hr-/- skin suggest that the normal balance of cell proliferation and differentiation is disrupted, supporting a model in which HR regulates the timing of epithelial cell differentiation in both the epidermis and hair follicle.
尽管哺乳动物无毛（Hr）基因的突变会导致小鼠和人类出现先天性脱发疾病，但Hr在皮肤生物学中的精确作用仍然未知。我们已经表明，Hr编码的蛋白质（HR）作为一种核受体共抑制因子发挥作用。为了研究HR在体内的作用，我们构建了一个功能缺失（Hr-/-）小鼠模型。Hr-/-小鼠的表型包括脱发和皮肤严重起皱。皮肤起皱与表皮细胞增殖增加和真皮囊肿的存在相关。此外，一个正常未分化的区域，即漏斗部，转变为维持表皮功能的形态学上不同的结构（椭圆囊）。基因表达分析显示，Hr-/-皮肤中角质形成细胞终末分化标志物和一种新的半胱天冬酶上调，证实了HR在体内作为共抑制因子的作用。体内形态学变化之前以及在培养的角质形成细胞中均出现基因表达差异，表明异常的转录调控导致了Hr-/-小鼠的表型。Hr-/-皮肤中存在的细胞类型特性表明，细胞增殖和分化的正常平衡被打破，支持了HR调节表皮和毛囊中上皮细胞分化时间的模型。
