Figure 4
(A) Homozygous Foxa1 knockout reduces urothelial proliferation in Upk2-HRAS* mice but has no impact on global expression of luminal gene expression markers. Immunohistochemistry for Foxa1 confirms KO, while Ki67 staining reveals reduced proliferation following Foxa1 homozygous KO. Conversely, heterozygous and homozygous Foxa1 KO had no impact on the staining patterns of the luminal markers Gata3 and or the basal marker Krt14. Fabp4 staining shifted from being predominantly nuclear and enriched in the umbrella cell population to being diffusely positive in HRAS* mutant mice with wild-type Foxa1 or heterozygous Foxa1 KO. Following Foxa1 KO, Fabp4 was predominantly nuclear. (B) Quantification of Ki67 in control and following UBC-CreERT2 induced knockout of one and two alleles of Foxa1. Compared to control tissue, Ki67 expression was significantly higher in heterozygous Upk2-HRAS* mice (P = 0.004; Kruskal-Wallis H test), as well as in heterozygous Upk2-HRAS* following UBC-CreERT2-mediated deletion of one allele of Foxa1 (P = 0.0007; Kruskal-Wallis H test). However, knockout of both alleles of Foxa1 in Upk2-HRAS* mice resulted in the detection of Ki67 levels similar to control (P = 0.16). Therefore, Foxa1 knockout results in reduced proliferation in the Upk2-HRAS* model of urothelial hyperplasia.
