4.7 Article

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

Journal

BRAIN
Volume 144, Issue 2, Pages 615-635

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/brain/awaa404

Keywords

nf1; rb1; tp53; glioma; zebrafish

Funding

  1. National Natural Science Foundation of China [81572494, 81872070]
  2. Natural Science Foundation of Guangdong Province [2015A030313440]
  3. Projects of Chongqing Science and Technology Committee [cstc2019jcyj-zdxmX0035, CSTCCXLJRC201714]
  4. Sanming Project of Medicine in Shenzhen [SZSM201911003]
  5. Shantou University
  6. Technion-Israel Institute of Technology

Ask authors/readers for more resources

The research indicates that combined deletions of nf1, tp53, and rb1 genes in zebrafish greatly promote gliomagenesis, with these glioma models showing relevance to temozolomide treatment.
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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available