WT and Get1 +/- Bladder Time Course

Skin and bladder epithelia form effective permeability barriers through the activation of distinct differentiation gene programs. Employing a genome-wide gene expression study, we identified transcription regulators whose expression correlates highly with that of differentiation markers both in bladder and skin, including the Grainyhead factor Get1/Grhl3, already known to be important for epidermal barrier formation. In the bladder, Get1 is most highly expressed in the differentiated umbrella cells and its mutation in mice leads to a defective bladder epithelial barrier formation due to failure of apical membrane specialization. Genes encoding components of the specialized urothelial membrane, the uroplakins, were downregulated in Get1-/- mice. At least one of these genes, Uroplakin II, is a direct target of Get1. The urothelial-specific activation of the Uroplakin II gene is due to selective binding of Get1 to the Uroplakin II promoter in urothelial cells, most likely regulated by histone modifications. These results demonstrate a key role for Get1 in urothelial differentiation and barrier formation. To gain insights into common and unique transcriptional regulatory programs during bladder differentiation, we profiled global gene expression in whole mouse bladder at E14.5, E16.5, and E18.5.皮肤与膀胱上皮通过激活特异性分化基因程序，构建起高效的通透性屏障。本研究通过全基因组基因表达分析，鉴定出在膀胱与皮肤组织中，表达水平与分化标志物高度相关的转录调控因子，其中包括Grainyhead家族因子Get1/Grhl3——该因子此前已被证实对表皮屏障形成具有关键作用。在膀胱组织中，Get1在已分化的伞状细胞中表达量最高；小鼠体内Get1突变会因顶端膜特化失败，导致膀胱上皮屏障形成缺陷。编码特化尿路上皮膜组分的尿斑蛋白（Uroplakins）的编码基因，在Get1基因敲除（Get1-/-）小鼠体内呈现表达下调。上述基因中至少有一个——尿斑蛋白II（Uroplakin II）——是Get1的直接靶基因。尿斑蛋白II基因的尿路上皮特异性激活，源于Get1在尿路上皮细胞中选择性结合该基因的启动子区域，这一过程大概率受组蛋白修饰调控。上述研究结果证实，Get1在尿路上皮分化与屏障形成过程中发挥关键调控作用。为深入解析膀胱分化过程中共有与特异的转录调控程序，本研究对胚胎发育阶段E14.5、E16.5及E18.5的小鼠全膀胱组织开展了全局基因表达谱分析。