Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1

Staci L. Solin, Heather R. Shive, Kevin D Woolard, Jeffrey J. Essner, Maura McGrail

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article number13745
JournalScientific Reports
Volume5
DOIs
StatePublished - Sep 8 2015

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Zebrafish
Neoplasms
Tumor Suppressor Genes
Transcription Activator-Like Effector Nucleases
Genetic Association Studies
Neuroglia
Vertebrates
Exons
Carcinogenesis
Embryonic Structures
Alleles
Messenger RNA
Brain

ASJC Scopus subject areas

  • General

Cite this

Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1. / Solin, Staci L.; Shive, Heather R.; Woolard, Kevin D; Essner, Jeffrey J.; McGrail, Maura.

In: Scientific Reports, Vol. 5, 13745, 08.09.2015.

Research output: Contribution to journalArticle

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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.",
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AU - McGrail, Maura

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