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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...

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Autores principales: Li, Yun-Fei, Cheng, Tao, Zhang, Ying-Jie, Fu, Xin-Xin, Mo, Jing, Zhao, Guo-Qin, Xue, Mao-Guang, Zhuo, Ding-Hao, Xing, Yan-Yi, Huang, Ying, Sun, Xiao-Zhi, Wang, Dan, Liu, Xiang, Dong, Yang, Zhu, Xiao-Sheng, He, Feng, Ma, Jun, Chen, Dong, Jin, Xi, Xu, Peng-Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624419/
https://www.ncbi.nlm.nih.gov/pubmed/36318514
http://dx.doi.org/10.1371/journal.pbio.3001856
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author Li, Yun-Fei
Cheng, Tao
Zhang, Ying-Jie
Fu, Xin-Xin
Mo, Jing
Zhao, Guo-Qin
Xue, Mao-Guang
Zhuo, Ding-Hao
Xing, Yan-Yi
Huang, Ying
Sun, Xiao-Zhi
Wang, Dan
Liu, Xiang
Dong, Yang
Zhu, Xiao-Sheng
He, Feng
Ma, Jun
Chen, Dong
Jin, Xi
Xu, Peng-Fei
author_facet Li, Yun-Fei
Cheng, Tao
Zhang, Ying-Jie
Fu, Xin-Xin
Mo, Jing
Zhao, Guo-Qin
Xue, Mao-Guang
Zhuo, Ding-Hao
Xing, Yan-Yi
Huang, Ying
Sun, Xiao-Zhi
Wang, Dan
Liu, Xiang
Dong, Yang
Zhu, Xiao-Sheng
He, Feng
Ma, Jun
Chen, Dong
Jin, Xi
Xu, Peng-Fei
author_sort Li, Yun-Fei
collection PubMed
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.
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spelling pubmed-96244192022-11-02 Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1 Li, Yun-Fei Cheng, Tao Zhang, Ying-Jie Fu, Xin-Xin Mo, Jing Zhao, Guo-Qin Xue, Mao-Guang Zhuo, Ding-Hao Xing, Yan-Yi Huang, Ying Sun, Xiao-Zhi Wang, Dan Liu, Xiang Dong, Yang Zhu, Xiao-Sheng He, Feng Ma, Jun Chen, Dong Jin, Xi Xu, Peng-Fei PLoS Biol Research Article 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. Public Library of Science 2022-11-01 /pmc/articles/PMC9624419/ /pubmed/36318514 http://dx.doi.org/10.1371/journal.pbio.3001856 Text en © 2022 Li et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Li, Yun-Fei
Cheng, Tao
Zhang, Ying-Jie
Fu, Xin-Xin
Mo, Jing
Zhao, Guo-Qin
Xue, Mao-Guang
Zhuo, Ding-Hao
Xing, Yan-Yi
Huang, Ying
Sun, Xiao-Zhi
Wang, Dan
Liu, Xiang
Dong, Yang
Zhu, Xiao-Sheng
He, Feng
Ma, Jun
Chen, Dong
Jin, Xi
Xu, Peng-Fei
Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1
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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624419/
https://www.ncbi.nlm.nih.gov/pubmed/36318514
http://dx.doi.org/10.1371/journal.pbio.3001856
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