PUBLICATION
Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1
- Authors
- Solin, S.L., Shive, H.R., Woolard, K.D., Essner, J.J., McGrail, M.
- ID
- ZDB-PUB-150909-7
- Date
- 2015
- Source
- Scientific Reports 5: 13745 (Journal)
- Registered Authors
- Essner, Jeffrey, McGrail, Maura
- Keywords
- none
- MeSH Terms
-
- Alleles
- Animals
- Germ Cells/metabolism
- Retinoblastoma Protein/chemistry
- Retinoblastoma Protein/genetics*
- Cell Transformation, Neoplastic/genetics*
- Gene Targeting*
- Sequence Alignment
- Genetic Loci
- Disease Models, Animal
- Brain Neoplasms/genetics
- Brain Neoplasms/pathology
- Zebrafish
- Humans
- Base Sequence
- Gene Silencing*
- Mitotic Index
- Endonucleases/metabolism*
- Gene Frequency
- PubMed
- 26345384 Full text @ Sci. Rep.
Citation
Solin, S.L., Shive, H.R., Woolard, K.D., Essner, J.J., McGrail, M. (2015) Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1. Scientific Reports. 5:13745.
Abstract
Investigating the in vivo role of tumor suppressor genes in cancer is technically challenging due to their essential requirement during early animal development. To address this bottleneck, we generated genetic mosaic adult zebrafish using TALEN genome editing and demonstrate somatic inactivation of the tumor suppressor retinoblastoma1 (rb1) induces tumorigenesis at high frequency. 11-33% of 1-cell stage embryos injected with TALEN mRNAs targeting rb1 exon 2 or 3 develop tumors beginning as early as 3.5 months of age. Lesions predominantly arise in the brain and show features of neuroectodermal-like and glial-like tumors. Mutant allele analysis is consistent with tumor initiation due to somatic inactivation of rb1, revealing a conserved role for rb1 in tumor suppression across vertebrates. In contrast to genetic mosaics, heterozygous rb1-/+ adults show no evidence of neoplasia, while homozygous mutant rb1-/- are larval lethal. This is the first demonstration that somatic inactivation of a tumor suppressor causes cancer in zebrafish, and highlights the utility of site-specific nucleases to create genetic mosaic zebrafish for tumor suppressor gene discovery. Somatic inactivation with site-directed nucleases in zebrafish presents a rapid and scalable strategy to study tumor suppressor gene function in cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping