PUBLICATION

Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish

Authors
Luo, J., Liu, P., Lu, C., Bian, W., Su, D., Zhu, C., Xie, S., Pan, Y., Li, N., Cui, W., Pei, D.S., Yang, X.
ID
ZDB-PUB-201208-50
Date
2020
Source
Brain : a journal of neurology   144(2): 615-635 (Journal)
Registered Authors
Keywords
glioma, nf1, rb1, tp53, zebrafish
Datasets
GEO:GSE129899
MeSH Terms
  • Signal Transduction*
  • Zebrafish
  • Tumor Suppressor Protein p53/metabolism
  • Mutation
  • Animals
  • Male
  • Brain Neoplasms/metabolism*
  • Brain Neoplasms/pathology
  • Neurofibromatosis 1/metabolism
  • Animals, Genetically Modified
  • Female
  • Retinoblastoma Protein/metabolism
  • Zebrafish Proteins/metabolism
  • Glioma/metabolism*
  • Glioma/pathology
(all 15)
PubMed
33279959 Full text @ Brain
Abstract
The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human gliomagenesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Marker Marker Type Name
Cas9EFGCas9
GFPEFGGFP
mCherryEFGmCherry
1 - 3 of 3
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Mapping
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Citation
Luo, J., Liu, P., Lu, C., Bian, W., Su, D., Zhu, C., Xie, S., Pan, Y., Li, N., Cui, W., Pei, D.S., Yang, X. (2020) Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish. Brain : a journal of neurology. 144(2):615-635.