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DNP63 regulates epithelial stratification and differentiation in the murine ureter

ABSTRACT: The urothelium is a stratified epithelium that lines the inner surface of the organs of the urinary drainage system. The urothelium consists of a layer of basal cells, one to several layers of intermediate cells, and an apical layer of large superficial cells. How this patterned arrangement of differentiated cell types arises from uncommitted precursor cells is insufficiently understood. Here, we analyzed the cellular and molecular function of the transcription factor DNP63. DNP63 expression begins in epithelial progenitors at embryonic day (E)14.5, and is confined to basal and intermediate cells from late fetal stages onwards. We show that in mice with a conditional loss of DNp63 in the ureter, the urothelium presents around birth as a monolayered but folded epithelium, consisting predominantly of partially differentiated superficial cells. At E15.5, i.e. shortly after the onset of DNP63 expression in the ureter, epithelial proliferation and cell division planes were unaffected. Transcriptional profiling revealed that DNp63 is required for the expression of genes that regulate epithelial stratification, cell adhesion and division. DNP63 is also responsible for repression of Ihh, precluding premature formation of the lamina propria. Analysis of mutant ureters at postnatal stages revealed a progressive reconstitution of the normal urothelial cytoarchitecture, suggesting that DNP63+ epithelial progenitors that have escaped recombination, undergo rapid proliferative expansion and differentiation into I and B cells. Our results suggest that a conserved DNP63 gene regulatory module is responsible for epithelial stratification, expansion of basal and intermediate cells, and correct differentiation of superficial cells in the murine ureter.

ORGANISM(S): Mus musculus

PROVIDER: GSE329129 | GEO | 2026/05/31

REPOSITORIES: GEO

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Project description:Peroxisome Proliferator-Activated Receptor-gamma (PPARG) is a nuclear hormone receptor that was originally described as a master regulator of adipogenesis but could also promote cellular differentiation in a number of epithelium. PPARG also serves as an important regulator in anti-inflammatory activity after a variety of injuries, acting in part by antagonizing the NF-kB pathway. Moreover, the expression of PPARG is strongly down regulated in the basal subtype of bladder cancer, suggesting that its removal might be essential in tumorigenesis. In urothelial cells, it has been shown that PPARG promotes urothelial differentiation in vitro, but its function in vivo remains unexplored. The urothelium is a stratified epithelium that serves as a barrier between the urinary tract and blood. It consists of terminally differentiated umbrella cells, intermediate cells which serve as umbrella cell progenitors; and unipotent basal cells. To determine the role of PPARG in vivo, we used Cre-Lox recombination to conditionally delete the Pparg gene in the mouse urothelium using the ShhCre driver, which drives recombination in basal and intermediate cells, and their respective daughters. Interestingly, ShhCre;Ppargfl/fl mutants lack umbrella and intermediate cells, but have an abnormal cell population negative for classical urothelial markers instead. Furthermore, we observed an increase of KRT14+ population in the basal compartment and squamous features in the mutant urothelium. Expression profile analysis suggested PPARG regulates metabolism, urothelial differentiation and innate immune response. We further challenged the Pparg mutant urothelium with acute injury. In wild type animals, urinary tract infection (UTI) with uropathogenic E.coli results in a transient innate immune response, followed by a completed regernation within 2 weeks. When ShhCre;Ppargfl/fl mutants were challenged with urinary tract infection, the innate immune response was not resolved even after several weeks and the Pparg ablated urothelium exhibited squamous metaplasia. RNAseq data suggested that PPARG plays a role in regulating squmous differentiation and NFkB signial pathway. Together these findings suggest that PPARG is essential for the normal differentiation of the urothelium and is a potent regulator of the inflammatory response after UTI. Understanding the link between the loss of PPARG, chronic inflammation and tumorigenesis in the urothelium could shed light on the urothelial differentiation network and pave the way for the development of therapeutic approaches to various urinary diseases.

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DNP63 regulates epithelial stratification and differentiation in the murine ureter

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