PUBLICATION

Zebrafish Hagoromo Mutants Up-Regulate fgf8 Postembryonically and Develop Neuroblastoma

Authors
Amsterdam, A., Lai, K., Komisarczuk, A.Z., Becker, T.S., Bronson, R.T., Hopkins, N., and Lees, J.A.
ID
ZDB-PUB-090622-8
Date
2009
Source
Molecular cancer research : MCR   7(6): 841-850 (Journal)
Registered Authors
Amsterdam, Adam, Becker, Thomas S., Hopkins, Nancy, Komisarczuk, Anna Zofia
Keywords
neural precursors, retrovirus, insertional mutagenesis, cancer
MeSH Terms
  • Animals
  • F-Box Proteins/biosynthesis*
  • F-Box Proteins/genetics
  • Fibroblast Growth Factors/biosynthesis
  • Fibroblast Growth Factors/genetics*
  • Gene Expression Regulation, Developmental
  • Genotype
  • Histocytochemistry
  • In Situ Hybridization
  • Mutagenesis, Insertional*
  • Neuroblastoma/genetics*
  • Neuroblastoma/metabolism
  • Polymerase Chain Reaction
  • Up-Regulation
  • Zebrafish
  • Zebrafish Proteins/biosynthesis*
  • Zebrafish Proteins/genetics*
PubMed
19531571 Full text @ Mol. Cancer Res.
Abstract
We screened an existing collection of zebrafish insertional mutants for cancer susceptibility by histologic examination of heterozygotes at 2 years of age. As most mutants had no altered cancer predisposition, this provided the first comprehensive description of spontaneous tumor spectrum and frequency in adult zebrafish. Moreover, the screen identified four lines, each carrying a different dominant mutant allele of Hagoromo previously linked to adult pigmentation defects, which develop tumors with high penetrance and that histologically resemble neuroblastoma. These tumors are clearly neural in origin, although they do not express catecholaminergic neuronal markers characteristic of human neuroblastoma. The zebrafish tumors result from inappropriate maintenance of a cell population within the cranial ganglia that are likely neural precursors. These neoplasias typically remain small but they can become highly aggressive, initially traveling along cranial nerves, and ultimately filling the head. The developmental origin of these tumors is highly reminiscent of human neuroblastoma. The four mutant Hagoromo alleles all contain viral insertions in the fbxw4 gene, which encodes an F-box WD40 domain-containing protein. However, although one allele clearly reduced the levels of fbxw4 mRNA, the other three insertions had no detectable effect on fbw4 expression. Instead, we showed that all four mutations result in the postembryonic up-regulation of the neighboring gene, fibroblast growth factor 8 (fgf8). Moreover, fgf8 is highly expressed in the tumorigenic lesions. Although fgf8 overexpression is known to be associated with breast and prostate cancer in mammals, this study provides the first evidence that fgf8 misregulation can lead to neural tumors. (Mol Cancer Res 2009;7(6):841-50).
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping