AUTHOR=Li Yaxin , Yu Minghui , Tan Lihong , Xue Shanshan , Du Xuanjin , Wu Xiaohui , Xu Hong , Shen Qian 

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

JOURNAL=Frontiers in Medicine

VOLUME=8

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.807898

DOI=10.3389/fmed.2021.807898

ISSN=2296-858X

ABSTRACT=<p>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. <italic>Robo2</italic> plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. <italic>Gen1</italic> 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 <italic>Robo2</italic> and <italic>Gen1</italic> using a <italic>piggyBac</italic> transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in <italic>Robo2</italic><sup><italic>PB</italic>/+</sup><italic>Gen1</italic><sup><italic>PB</italic>/+</sup> mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the <italic>Robo2</italic><sup><italic>PB</italic>/+</sup><italic>Gen1</italic><sup><italic>PB</italic>/+</sup> mice during the embryonic period. <italic>Robo2</italic> and <italic>Gen1</italic> 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.</p>