PPARG contributes to urothelial integrity in the murine ureter by activating the expression of Shh and superficial cell-specific genes

TL;DR

PPARG helps maintain the structure of the mouse ureter by activating genes in different layers of the urothelium.

Contribution

This study reveals PPARG's dual role in activating Shh and superficial cell-specific genes for urothelial integrity.

Findings

Pparg deletion in ureteric epithelium leads to a dilated ureter with undifferentiated luminal and proliferating basal cells.

Pharmacological SHH activation in Pparg-deficient ureters restores normal urothelial structure and cell numbers.

PPARG independently activates structural genes in superficial cells and Shh in basal and intermediate cells.

Abstract

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.

Summary: PPARG is required for Shh expression in the basal and intermediate cell layer of the mouse ureteric epithelium and for expression of many genes in the superficial layer, ensuring the formation of a three-layered, quiescent urothelium.

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