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

Scientific Reports
Staci L SolinMaura McGrail

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 ...Continue Reading

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Citations

Oct 27, 2016·Cell Reports·Katarzyna ModzelewskaRodney A Stewart
Apr 17, 2018·Médecine sciences : M/S·Pamela VölkelPierre-Olivier Angrand
Nov 11, 2017·Clinical and Translational Medicine·Sonya StenfeltHenrik Boije
Sep 13, 2017·Frontiers in Oncology·Stefanie KirchbergerMartin Distel
Aug 8, 2020·Cancers·Ludivine RabyPierre-Olivier Angrand
Mar 5, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Aaron L SarverTimothy C Hallstrom
Aug 17, 2021·Bio-protocol·Jordan M WelkerMaura McGrail

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Methods Mentioned

BETA
transgenic
gene knockouts
gene knockout
dissection
PCR

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