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Background  Disruption of ROBO2 in humans causes vesicoureteral reflux (VUR)/congenital anomalies of the kidney and urinary tract (CAKUT).  PiggyBac  (PB) is a DNA transposon, and its insertion often reduces—but does not eliminate—gene expression. The  Robo2  insertion mutant exhibited non-dilating VUR, ureteropelvic junction obstruction (UPJO) not found in reported models. We studied the incidence and outcomes of VUR/CAKUT in this mutant and explored the relationship between  Robo2  gene expression and the occurrence and severity of VUR/CAKUT.    Methods  The urinary systems of newborn mutants were evaluated via Vevo 770 micro-ultrasound. Some of the normal animals—and all of the abnormal animals—were followed to adulthood and tested for VUR. Urinary obstruction experiments were performed on mice with hydronephrosis. The histology of the kidney and ureter was examined by light microscopy and transmission electron microscopy.  Robo2   PB / PB   mice were crossed with  Hoxb7 / myr - Venus  mice to visualize the location of the ureters relative to the bladder.    Results  In  Robo2   PB / PB   mice, PB insertion led to an approximately 50 % decrease in Robo2 gene expression. The most common (27.07 %, 62/229) abnormality was non-dilating VUR, and no statistically significant differences were found between age groups. Approximately 6.97 % displayed ultrasound-detectable CAKUT, and these mice survived to adulthood without improvement. No severe CAKUT were found in  Robo2   PB /+  mice. The refluxing ureters showed disorganized smooth muscle fibers, reduced muscle cell populations, intercellular edema and intracytoplasmic vacuoles in smooth muscle cells. Both UPJ and UVJ muscle defects were noted in  Robo2   PB / PB   mice.    Conclusions   Robo2   PB / PB   mice is the first  Robo2 -deficient mouse model to survive to adulthood while displaying non-dilating VUR, UPJO, and multiple ureters with blind endings. The genetic background of these mutants may influence the penetrance and severity of the CAKUT phenotypes. VUR and other CAKUT found in this mutant had little chance of spontaneous resolution, and this requires careful follow-up. We reported for the first time that the non-dilated refluxing ureters showed disorganized smooth muscle fibers and altered smooth muscle cell structure, more accurately mimicking the characteristics of human cases. Future studies are required to test the role of  Robo2  in the ureteric smooth muscle.

New congenital anomalies of the kidney and urinary tract and outcomes in Robo2 mutant mice with the inserted piggyBac transposon