Wnt5a controls ureterovesical junction formation by modulating Shh

Yun K, Hall MD and Perantoni AO

National Cancer Institute, Frederick, MD 21702 USA.

Ureterovesical junction formation depends upon a series of morphogenetic events which begins with the insertion of the nephric duct into the cloacal epithelium and apoptotic degeneration of the common nephric duct at the urogenital sinus and ends with the repositioning of the ureter and its subsequent connection with the bladder. Mutations in Wnt5a or its predominant receptor Ror2result in hydronephrosis/hydroureter due to a failed ureterovesical connection, but how Wnt5a regulates the ureter maturation process has not been established. Here we determine the underlying mechanism responsible for this abnormality in the mouse. The initial insertion of the nephric duct into the cloacal epithelium occurred normally in Wnt5a mutants. However, deletion of Wnt5aprior to E10.5 in the cloacal region led to a persistent common nephric duct during ureter maturation by reducing cell death in the duct. Concomitant with Wnt5a loss, Shh expression in the cloacal epithelium was increased in mutants, and Shh haploinsufficiency rescued cell death in the common nephric duct and suppressed the hydronephrosis/hydroureter phenotype. Furthermore, constitutive activation of Shh activity in the cloacal region induced the hydronephrosis/hydroureter phenotype and caused a reduction of cell death in the common nephric duct, suggesting that Wnt5a functions, at least in part, through its inhibition of Shh. This study identifies a new mechanism for ureterovesical junction formation that is dependent on the regulation of cell death in the nephric duct and implicates Wnt5a in the repression of Shh in the cloacal epithelium to facilitate degeneration of the common nephric duct and ureter insertion.