Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice
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...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2021.807898/full |
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| author | Yaxin Li Minghui Yu Lihong Tan Shanshan Xue Xuanjin Du Xiaohui Wu Xiaohui Wu Hong Xu Qian Shen |
| author_facet | Yaxin Li Minghui Yu Lihong Tan Shanshan Xue Xuanjin Du Xiaohui Wu Xiaohui Wu Hong Xu Qian Shen |
| author_sort | Yaxin Li |
| collection | DOAJ |
| description | 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 Robo2PB/+Gen1PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2PB/+Gen1PB/+ 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. |
| first_indexed | 2024-12-20T15:36:38Z |
| format | Article |
| id | doaj.art-b32d447350d54fd28af51a7e8ccde0c4 |
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| issn | 2296-858X |
| language | English |
| last_indexed | 2024-12-20T15:36:38Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Medicine |
| spelling | doaj.art-b32d447350d54fd28af51a7e8ccde0c42022-12-21T19:35:23ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2022-01-01810.3389/fmed.2021.807898807898Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in MiceYaxin Li0Minghui Yu1Lihong Tan2Shanshan Xue3Xuanjin Du4Xiaohui Wu5Xiaohui Wu6Hong Xu7Qian Shen8Department of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaState 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, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaDepartment of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, ChinaCongenital 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 Robo2PB/+Gen1PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2PB/+Gen1PB/+ 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.https://www.frontiersin.org/articles/10.3389/fmed.2021.807898/fullRobo2GEN1congenital anomalies of the kidney and urinary tractGDNF/REToligo-/polygenic disease |
| spellingShingle | Yaxin Li Minghui Yu Lihong Tan Shanshan Xue Xuanjin Du Xiaohui Wu Xiaohui Wu Hong Xu Qian Shen Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice Frontiers in Medicine Robo2 GEN1 congenital anomalies of the kidney and urinary tract GDNF/RET oligo-/polygenic disease |
| title | Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice |
| title_full | Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice |
| title_fullStr | Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice |
| title_full_unstemmed | Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice |
| title_short | Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice |
| title_sort | robo2 and gen1 coregulate ureteric budding by activating the mapk erk signaling pathway in mice |
| topic | Robo2 GEN1 congenital anomalies of the kidney and urinary tract GDNF/RET oligo-/polygenic disease |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2021.807898/full |
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