Disruption ofGen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice

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 disru...

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Bibliographic Details
Published in:International journal of biological sciences 2018-01, Vol.14 (1), p.10
Main Authors: Wang, Herui, Zhang, Chi, Wang, Xiaowen, Lian, Yaru, Guo, Bin, Han, Miao, Zhang, Xiaoe, Zhu, Xiaoting, Xu, Sixian, Guo, Zengli, Bi, Yunli, Shen, Qian, Wang, Xiang, Liu, Jiaojiao, Zhuang, Yuan, Ni, Ting, Xu, Hong, Wu, Xiaohui
Format: Article
Language:English
Subjects:
Congenital anomalies
Congenital defects
Etiology
Glial cell line-derived neurotrophic factor
Kidneys
Pax2 protein
Resolvase
SIX gene family
Transcription
Ureter
Urinary tract
Urogenital system
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Summary: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.
ISSN:1449-2288
DOI:10.7150/ijbs.22768