Rudat Carsten, Straube Philipp, Hegermann Jan, Trowe Mark-Oliver, Thiesler Hauke, Hildebrandt Herbert, Witt Lisa, Kispert Andreas
Institute of Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.
Institute of Functional and Applied Anatomy, Research Core Unit Electron Microscopy, Hannover Medical School, 30625 Hannover, Germany.
Development. 2025 Apr 15;152(8). doi: 10.1242/dev.204324. Epub 2025 Apr 17.
The urothelium is a stratified epithelium with an important barrier function in the urinary drainage system. The differentiation and maintenance of the three major urothelial cell types (basal, intermediate and superficial cells) is incompletely understood. Here, we show that mice with a conditional deletion of the transcription factor gene peroxisome proliferator activated receptor gamma (Pparg) in the ureteric epithelium have a dilated ureter at postnatal stages with a urothelium consisting of a layer of undifferentiated luminal cells and a layer of proliferating basal cells. Molecular analysis of fetal stages revealed that the expression of a large number of genes is not activated in superficial cells and that of a few genes, including Shh, is not activated in intermediate and basal cells. Pharmacological activation of SHH signaling in explant cultures of perinatal Pparg-deficient ureters reduced ureteral width and urothelial cell number to normal levels, increased the number of intermediate cells and slightly reduced basal cell proliferation. Our data suggest that PPARG independently activates the expression of structural genes in superficial cells and of Shh in basal and intermediate cells, and that both functions contribute to urothelial integrity.
尿路上皮是一种复层上皮，在尿液引流系统中具有重要的屏障功能。三种主要尿路上皮细胞类型（基底细胞、中间细胞和表层细胞）的分化和维持机制尚未完全明确。在此，我们发现输尿管上皮中条件性缺失转录因子基因过氧化物酶体增殖物激活受体γ（Pparg）的小鼠在出生后阶段输尿管扩张，其尿路上皮由一层未分化的腔面细胞和一层增殖的基底细胞组成。对胎儿阶段的分子分析显示，大量基因在表层细胞中未被激活，少数基因（包括Shh）在中间细胞和基底细胞中未被激活。在围产期Pparg缺陷型输尿管的外植体培养物中对SHH信号进行药理学激活，可使输尿管宽度和尿路上皮细胞数量恢复至正常水平，增加中间细胞数量，并略微降低基底细胞增殖。我们的数据表明，PPARG独立激活表层细胞中结构基因的表达以及基底细胞和中间细胞中Shh的表达，这两种功能都有助于尿路上皮的完整性。
