Int J Biol Sci 2020; 16(9):1640-1647. doi:10.7150/ijbs.42855 This issue

Research Paper

Gen1 mutation caused kidney hypoplasia and defective ureter-bladder connections in mice

Xiaowen Wang1, Herui Wang2, Jiaojiao Liu3, Yinv Gong3, Chi Zhang4, Francia Fang5, Aiguo Li2, Xiaohui Wu3,6, Qian Shen3, Hong Xu3✉

1. Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430000, China
2. Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
3. Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai 201102, China
4. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
5. University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
6. State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China

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Wang X, Wang H, Liu J, Gong Y, Zhang C, Fang F, Li A, Wu X, Shen Q, Xu H. Gen1 mutation caused kidney hypoplasia and defective ureter-bladder connections in mice. Int J Biol Sci 2020; 16(9):1640-1647. doi:10.7150/ijbs.42855. Available from

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Graphic abstract

Limited genetic factors were uncovered for the development of congenital anomalies of the kidney and urinary tract (CAKUT). We previously reported that a Holliday junction resolvase Gen1 was essential for early metanephric development in mice. This comprehensive follow-up study focused on the roles of Gen1 in late metanephric development. We found that Gen1 mutation impaired the late development of both kidney and urinary tract. In vivo and ex-vivo kidney primordia culture confirmed decreased ureteric bud branching in Gen1 mutants, which consequently caused hypoplasia. We also observed abnormal urinary tract development. Programmed apoptosis at the end of nephric duct disappeared in Gen1 mutants, which caused abnormal ureter-bladder connections, leading to vesicoureteral reflux (VUR) or ureterovesical junction obstruction (UVJO). Mechanistically, RNA-seq analysis proved that Gen1 mutation impaired the expression of multiple regulatory genes for the metanephric development, including Six2. Taken together, our study provides more insight into the roles of Gen1 in the development of the kidney and urinary tract, which may have potential clinical significance in the treatment and/or prevention of CAKUT.