Disruption of the Dapper3 Gene Aggravates Ureteral Obstruction-mediated Renal Fibrosis by Amplifying Wnt/β-catenin Signaling

Wnt/β-catenin signaling plays key roles in embryonic development and tissue homeostasis. Dapper3/Dact3, one of the three members of the Dapper gene family, is transcriptionally repressed in colorectal cancer and may function as a negative regulator of Wnt/β-catenin signaling. To investigate its physiological functions, we generated a mouse strain harboring conditional null alleles of Dapper3 (Dapper3(flox/flox)), and homozygous Dapper3-deficient (Dapper3(-/-)) mice were produced after crossing with EIIa-cre transgenic mice. We found that Dapper3 is not essential for mouse embryogenesis, postnatal survival, and reproduction. However, adult Dapper3(-/-) mice exhibited a mild reduction in body weight compared with their wild-type littermates, suggesting a functional role of Dapper3 in postnatal growth. To investigate the role of Dapper3 in renal fibrosis, we employed the unilateral ureteral obstruction model. Dapper3 mRNA expression was up-regulated in kidney after unilateral ureteral obstruction. Loss of the Dapper3 gene enhanced myofibroblast activation and extracellular matrix overproduction in the obstructed kidney. Moreover, this aggravated fibrotic phenotype was accompanied with accumulation of Dishevelled2 and β-catenin proteins and activation of Wnt-targeted fibrotic genes. In primary renal tubular cells, Dapper3 inhibits Wnt-induced epithelial-to-mesenchymal transition. Consistently, Dapper3 interacted with and down-regulated Dishevelled2 protein and attenuated the Wnt-responsive Topflash reporter expression. These findings together suggest that Dapper3 antagonizes the fibrotic actions of Wnt signaling in kidney.