PUBLICATION

Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1

Authors
Li, Y.F., Cheng, T., Zhang, Y.J., Fu, X.X., Mo, J., Zhao, G.Q., Xue, M.G., Zhuo, D.H., Xing, Y.Y., Huang, Y., Sun, X.Z., Wang, D., Liu, X., Dong, Y., Zhu, X.S., He, F., Ma, J., Chen, D., Jin, X., Xu, P.F.
ID
ZDB-PUB-221102-6
Date
2022
Source
PLoS Biology   20: e3001856 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Microcephaly*/genetics
  • Animals
  • N-Myc Proto-Oncogene Protein
  • Leucine
  • Zebrafish*/metabolism
  • TOR Serine-Threonine Kinases/metabolism
(all 6)
PubMed
36318514 Full text @ PLoS Biol.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf3097TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    mycnCRISPR6-mycnCRISPR
    mycnCRISPR1-mycnCRISPR
    mycnCRISPR2-mycnCRISPR
    mycnCRISPR3-mycnCRISPR
    mycnCRISPR4-mycnCRISPR
    mycnCRISPR5-mycnCRISPR
    1 - 6 of 6
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    Fish
    No data available
    Antibodies
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
    Show
    Mapping
    No data available
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    Citation
    Li, Y.F., Cheng, T., Zhang, Y.J., Fu, X.X., Mo, J., Zhao, G.Q., Xue, M.G., Zhuo, D.H., Xing, Y.Y., Huang, Y., Sun, X.Z., Wang, D., Liu, X., Dong, Y., Zhu, X.S., He, F., Ma, J., Chen, D., Jin, X., Xu, P.F. (2022) Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1. PLoS Biology. 20:e3001856.