Perinatal Institute of Cincinnati Children's Hospital Medical Center, Division of Neonatology-Perinatal-Pulmonary Biology, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Dev Biol. 2011 Oct 1;358(1):79-90. doi: 10.1016/j.ydbio.2011.07.020. Epub 2011 Jul 22.
Kruppel-like transcription factor 5 (Klf5) was detected in the developing and mature murine bladder urothelium. Herein we report a critical role of KLF5 in the formation and terminal differentiation of the urothelium. The Shh(GfpCre) transgene was used to delete the Klf5(floxed) alleles from bladder epithelial cells causing prenatal hydronephrosis, hydroureter, and vesicoureteric reflux. The bladder urothelium failed to stratify and did not express terminal differentiation markers characteristic of basal, intermediate, and umbrella cells including keratins 20, 14, and 5, and the uroplakins. The effects of Klf5 deletion were unique to the developing bladder epithelium since maturation of the epithelium comprising the bladder neck and urethra was unaffected by the lack of KLF5. mRNA analysis identified reductions in Pparγ, Grhl3, Elf3, and Ovol1expression in Klf5 deficient fetal bladders supporting their participation in a transcriptional network regulating bladder urothelial differentiation. KLF5 regulated expression of the mGrhl3 promoter in transient transfection assays. The absence of urothelial Klf5 altered epithelial-mesenchymal signaling leading to the formation of an ectopic alpha smooth muscle actin positive layer of cells subjacent to the epithelium and a thinner detrusor muscle that was not attributable to disruption of SHH signaling, a known mediator of detrusor morphogenesis. Deletion of Klf5 from the developing bladder urothelium blocked epithelial cell differentiation, impaired bladder morphogenesis and function causing hydroureter and hydronephrosis at birth.
Kruppel 样转录因子 5（Klf5）在发育中和成熟的鼠膀胱尿路上皮中被检测到。在此，我们报告了 KLF5 在尿路上皮的形成和终末分化中的关键作用。使用 Shh(GfpCre) 转基因从膀胱上皮细胞中删除 Klf5（floxed）等位基因，导致产前肾积水、输尿管积水和膀胱输尿管反流。膀胱尿路上皮未能分层，并且不表达基底细胞、中间细胞和伞细胞的终末分化标志物，包括角蛋白 20、14 和 5 和尿路上皮蛋白。Klf5 缺失的影响是发育中的膀胱上皮所特有的，因为组成膀胱颈部和尿道的上皮的成熟不受缺乏 KLF5 的影响。mRNA 分析鉴定出 Klf5 缺失的胎儿膀胱中 Pparγ、Grhl3、Elf3 和 Ovol1 表达减少，支持它们参与调节膀胱尿路上皮分化的转录网络。KLF5 在瞬时转染测定中调节 mGrhl3 启动子的表达。尿路上皮 Klf5 的缺失改变了上皮-间充质信号，导致位于上皮下方的异位α平滑肌肌动蛋白阳性细胞层和更薄的逼尿肌的形成，这归因于 SHH 信号的破坏，SHH 信号是逼尿肌形态发生的已知介质。从发育中的膀胱尿路上皮中删除 Klf5 阻止了上皮细胞分化，损害了膀胱形态发生和功能，导致出生时出现输尿管积水和肾积水。
