Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1
Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome’s pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a z...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-11-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624419/?tool=EBI |
| _version_ | 1798044661773762560 |
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| author | Yun-Fei Li Tao Cheng Ying-Jie Zhang Xin-Xin Fu Jing Mo Guo-Qin Zhao Mao-Guang Xue Ding-Hao Zhuo Yan-Yi Xing Ying Huang Xiao-Zhi Sun Dan Wang Xiang Liu Yang Dong Xiao-Sheng Zhu Feng He Jun Ma Dong Chen Xi Jin Peng-Fei Xu |
| author_facet | Yun-Fei Li Tao Cheng Ying-Jie Zhang Xin-Xin Fu Jing Mo Guo-Qin Zhao Mao-Guang Xue Ding-Hao Zhuo Yan-Yi Xing Ying Huang Xiao-Zhi Sun Dan Wang Xiang Liu Yang Dong Xiao-Sheng Zhu Feng He Jun Ma Dong Chen Xi Jin Peng-Fei Xu |
| author_sort | Yun-Fei Li |
| collection | DOAJ |
| description | Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome’s pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease. A new mycn mutant zebrafish model of Feingold syndrome type 1 recapitulates many aspects of the human disease, including intestinal defects. This model provides insights into the mechanisms of the disorder, revealing altered mTOR signaling, changes in ribosomal biosynthesis and assembly, and decreased proliferation. Targeting TOR signaling ameliorated some of the intestinal pathologies. |
| first_indexed | 2024-04-11T23:07:52Z |
| format | Article |
| id | doaj.art-aafc302a49fc4ce3a6f527d7a12cf09e |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-11T23:07:52Z |
| publishDate | 2022-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-aafc302a49fc4ce3a6f527d7a12cf09e2022-12-22T03:57:57ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852022-11-012011Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1Yun-Fei LiTao ChengYing-Jie ZhangXin-Xin FuJing MoGuo-Qin ZhaoMao-Guang XueDing-Hao ZhuoYan-Yi XingYing HuangXiao-Zhi SunDan WangXiang LiuYang DongXiao-Sheng ZhuFeng HeJun MaDong ChenXi JinPeng-Fei XuFeingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome’s pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease. A new mycn mutant zebrafish model of Feingold syndrome type 1 recapitulates many aspects of the human disease, including intestinal defects. This model provides insights into the mechanisms of the disorder, revealing altered mTOR signaling, changes in ribosomal biosynthesis and assembly, and decreased proliferation. Targeting TOR signaling ameliorated some of the intestinal pathologies.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624419/?tool=EBI |
| spellingShingle | Yun-Fei Li Tao Cheng Ying-Jie Zhang Xin-Xin Fu Jing Mo Guo-Qin Zhao Mao-Guang Xue Ding-Hao Zhuo Yan-Yi Xing Ying Huang Xiao-Zhi Sun Dan Wang Xiang Liu Yang Dong Xiao-Sheng Zhu Feng He Jun Ma Dong Chen Xi Jin Peng-Fei Xu Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 PLoS Biology |
| title | Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 |
| title_full | Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 |
| title_fullStr | Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 |
| title_full_unstemmed | Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 |
| title_short | Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 |
| title_sort | mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of feingold syndrome 1 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624419/?tool=EBI |
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