Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice

Congenital anomalies of the kidney and urinary tract (CAKUT) are some of the most common developmental defects and have a complicated etiology, indicating an interaction of (epi-) genetic and environmental factors. Single gene mutations and copy number variations (CNVs) do not explain most cases of CAKUT, and simultaneous contributions of more than one gene (di-, oligo-, or polygenic effects; i.e., complex genetics) may lead to the pathogenesis of CAKUT. Robo2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. Gen1 is a candidate gene associated with CAKUT because of its important role in early metanephric development in mice. We established a mouse model with double disruption of Robo2 and Gen1 using a piggyBac transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in Robo2PB/+Gen1PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2PB/+Gen1PB/+ mice during the embryonic period. Robo2 and Gen1 exert synergistic effects on mouse kidney development, promoting cell proliferation by activating the GDNF/RET pathway and downstream MAPK/ERK signaling. Our findings provide a disease model for CAKUT as an oligogenic disorder.

Pediatric Genitourinary Radiology

Chapter 13 examines radiologic images for common and uncommon pediatric genitourinary disorders. These include pediatric congenital disorders such as renal agenesis, autosomal recessive polycystic kidney disease, multicystic dysplastic kidney, horseshoe kidney/cross-fused ectopia, prune belly syndrome, congenital uteropelvic junction obstruction, vesicoureteral reflux, duplicated collecting system, ureterocele, urachal anomalies, bladder exstrophy, and posterior urethral valves. The chapter goes on to look at neuroblastoma and Wilms tumor. Reproductive disorders are also examined, such as ovarian torsion, testicular torsion, epididymo-orchitis, hydrocele, varicocele, testicular tumors, and sacrococcygeal teratoma. This chapter covers the clinical features and anatomy associated with these disorders as well as their diagnosis based on radiologic imaging.