Disruption of Gen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice

Herui Wang; Chi Zhang; Xiaowen Wang; Yaru Lian; Bin Guo; Miao Han; Xiaoe Zhang; Xiaoting Zhu; Sixian Xu; Zengli Guo; Yunli Bi; Qian Shen; Xiang Wang; Jiaojiao Liu; Yuan Zhuang; Ting Ni; Hong Xu; Xiaohui Wu

doi:10.7150/ijbs.22768

Disruption of Gen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice

Int J Biol Sci. 2018 Jan 1;14(1):10-20. doi: 10.7150/ijbs.22768. eCollection 2018.

Authors

Herui Wang^{1

2

3}, Chi Zhang^{1

2

4}, Xiaowen Wang^{2

5}, Yaru Lian^{1

6}, Bin Guo¹, Miao Han^{1

6}, Xiaoe Zhang², Xiaoting Zhu¹, Sixian Xu¹, Zengli Guo¹, Yunli Bi², Qian Shen², Xiang Wang², Jiaojiao Liu², Yuan Zhuang^{1

7}, Ting Ni^{1

6}, Hong Xu², Xiaohui Wu^{1

2}

Affiliations

¹ 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.
² Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai 201102, China.
³ Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
⁵ Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430000, China.
⁶ MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200433, China.
⁷ Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common developmental defects in humans. Despite of several known CAKUT-related loci (HNF1B, PAX2, EYA1, etc.), the genetic etiology of CAKUT remains to be elucidated for most patients. In this study, we report that disruption of the Holliday Junction resolvase gene Gen1 leads to renal agenesis, duplex kidney, hydronephrosis, and vesicoureteral reflux (VUR) in mice. GEN1 interacts with SIX1 and enhances the transcriptional activity of SIX1/EYA1, a key regulatory complex of the GDNF morphogen. Gen1 mutation impairs Grem1 and Gdnf expression, resulting in excessive ureteric bud formation and defective ureteric bud branching during early kidney development. These results revealed an unidentified role of GEN1 in kidney development and suggested its contribution to CAKUT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
HEK293 Cells
Holliday Junction Resolvases / genetics
Holliday Junction Resolvases / metabolism*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Immunoprecipitation
In Situ Hybridization
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Kidney / abnormalities*
Kidney / metabolism*
Mice
Mutation
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Polymerase Chain Reaction
Protein Binding
Protein Tyrosine Phosphatases / genetics
Protein Tyrosine Phosphatases / metabolism
Urinary Tract / abnormalities*
Urinary Tract / metabolism*

Substances

GEN1 protein, mouse
Homeodomain Proteins
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Six1 protein, mouse
Holliday Junction Resolvases
Eya1 protein, mouse
Protein Tyrosine Phosphatases