and 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. plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. 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 and using a transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the mice during the embryonic period. and 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.