Patel Satyakam, Xi Zong Fang, Seo Eun Young, McGaughey David, Segre Julia A
National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18668-73. doi: 10.1073/pnas.0608658103. Epub 2006 Nov 27.
Premature infants are at an increased risk for infections and dehydration because of incomplete development of the epidermis, which attains its essential function as a barrier only during the last stages of in utero development. When a premature birth is anticipated, antenatal corticosteroids are administered to accelerate lung epithelium differentiation. One pleiotropic, but beneficial, effect of antenatal corticosteroids is acceleration of skin barrier establishment by an unknown mechanism. In mice, the transcription factor Klf4 is both necessary and sufficient, within a developmental field of competence, to establish this skin barrier, as demonstrated by targeted ablation and transgenic expression of Klf4, respectively. Here, we report that Klf4 and corticosteroid treatment coordinately accelerate barrier acquisition in vivo. Transcriptional profiling reveals that the genes regulated by corticosteroids and Klf4 during the critical window of epidermal development significantly overlap. KLF4 activates the proximal promoters of a significant subset of these genes. Dissecting the intersection of the genetic and pharmacological pathways, regulated by KLF4 and corticosteroids, respectively, leads to a mechanistic understanding of the normal process of epidermal development in utero.
由于表皮发育不完全，早产儿感染和脱水的风险增加，而表皮仅在子宫内发育的最后阶段才获得其作为屏障的基本功能。当预计会早产时，会给予产前皮质类固醇以加速肺上皮细胞分化。产前皮质类固醇的一个多效但有益的作用是通过未知机制加速皮肤屏障的建立。在小鼠中，转录因子Klf4在一个发育能力范围内对于建立这种皮肤屏障既是必需的也是充分的，分别通过Klf4的靶向消融和转基因表达得到了证明。在此，我们报告Klf4和皮质类固醇治疗在体内协同加速屏障的获得。转录谱分析表明，在表皮发育的关键窗口期，由皮质类固醇和Klf4调控的基因有显著重叠。KLF4激活了这些基因中相当一部分的近端启动子。剖析分别由KLF4和皮质类固醇调控的遗传和药理途径的交集，有助于对子宫内表皮发育的正常过程形成机制性理解。
