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*
  • Tumor Suppressor Protein p53/metabolism
  • Female
  • Brain Neoplasms/metabolism*
  • Brain Neoplasms/pathology
  • Zebrafish Proteins/metabolism
  • Male
  • Glioma/metabolism*
  • Glioma/pathology
  • Retinoblastoma Protein/metabolism
  • Neurofibromatosis 1/metabolism
  • Animals
  • Mutation
  • Animals, Genetically Modified
  • Zebrafish
(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
Figure Gallery (8 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mi2001TgTransgenic Insertion
    zf3453a
      Unknown
      zf3453TgTransgenic Insertion
        zf3454a
          Unknown
          zf3454TgTransgenic Insertion
            zf3455a
              Unknown
              zf3455TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                nf1aCRISPR3-nf1aCRISPR
                nf1bCRISPR2-nf1bCRISPR
                rb1CRISPR6-rb1CRISPR
                tp53CRISPR12-tp53CRISPR
                1 - 4 of 4
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                Fish
                Antibodies
                No data available
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                Cas9EFGCas9
                GFPEFGGFP
                mCherryEFGmCherry
                1 - 3 of 3
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                Mapping
                No data available