Pparg drives luminal differentiation and luminal tumor formation in the urothelium

We find that Pparg is a master regulator of cell specification during urothelial homeostasis, driving a luminal differentiation program via retinoid signaling. Interestingly, expression of activated Pparg in basal cells only drives tumor formation when they are in an activated state, that are in an activated state, induces formation of luminal tumors with papillary morphology, Expression of an activated form of Pparg induces basal cells at homeostasis, to differentiate directly into luminal cells. In a BBN mouse model which produces basal subtypes tumors in wild type animals, activated Pparg drives formation of luminal tumors, suggesting that this transcription factor is a master regulator of luminal differentiation, as has been suggested from in vitro studies. Overall design: mRNA profiles of WT and K5VP16;Pparg mutant urothelial cells

我们发现，过氧化物酶体增殖物激活受体γ（Pparg）是尿路上皮稳态过程中细胞特化的主调控因子，通过维甲酸信号通路调控腔面分化程序。值得注意的是，仅当基底细胞处于激活状态时，在基底细胞中表达激活型Pparg方可诱导肿瘤形成，并生成具有乳头状形态的腔面型肿瘤。表达激活型Pparg可促使处于稳态的基底细胞直接分化为腔面细胞。在野生型（WT）小鼠体内可诱导产生基底亚型肿瘤的BBN小鼠模型中，激活型Pparg可驱动腔面型肿瘤的形成，这表明该转录因子是腔面分化的主调控因子，这与体外研究的推测一致。实验整体设计：野生型（WT）与K5VP16；Pparg突变型尿路上皮细胞的mRNA表达谱