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

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

doi:10.3389/fmed.2021.807898

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

Front Med (Lausanne). 2022 Jan 5:8:807898. doi: 10.3389/fmed.2021.807898. eCollection 2021.

Authors

Yaxin Li¹, Minghui Yu¹, Lihong Tan¹, Shanshan Xue¹, Xuanjin Du¹, Xiaohui Wu^{1

2}, Hong Xu¹, Qian Shen¹

Affiliations

¹ Department of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.
² State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.

Abstract

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 Robo2 ^PB/+ Gen1 ^PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2 ^PB/+ Gen1 ^PB/+ 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.

Keywords: GDNF/RET; GEN1; Robo2; congenital anomalies of the kidney and urinary tract; oligo-/polygenic disease.