Cargando…
Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1
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...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642565/ https://www.ncbi.nlm.nih.gov/pubmed/26345384 http://dx.doi.org/10.1038/srep13745 |
_version_ | 1782400380653535232 |
---|---|
author | Solin, Staci L. Shive, Heather R. Woolard, Kevin D. Essner, Jeffrey J. McGrail, Maura |
author_facet | Solin, Staci L. Shive, Heather R. Woolard, Kevin D. Essner, Jeffrey J. McGrail, Maura |
author_sort | Solin, Staci L. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4642565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46425652015-11-20 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 Sci Rep Article 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. Nature Publishing Group 2015-09-08 /pmc/articles/PMC4642565/ /pubmed/26345384 http://dx.doi.org/10.1038/srep13745 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Solin, Staci L. Shive, Heather R. Woolard, Kevin D. Essner, Jeffrey J. McGrail, Maura Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
title | Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
title_full | Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
title_fullStr | Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
title_full_unstemmed | Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
title_short | Rapid tumor induction in zebrafish by TALEN-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
title_sort | rapid tumor induction in zebrafish by talen-mediated somatic inactivation of the retinoblastoma1 tumor suppressor rb1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642565/ https://www.ncbi.nlm.nih.gov/pubmed/26345384 http://dx.doi.org/10.1038/srep13745 |
work_keys_str_mv | AT solinstacil rapidtumorinductioninzebrafishbytalenmediatedsomaticinactivationoftheretinoblastoma1tumorsuppressorrb1 AT shiveheatherr rapidtumorinductioninzebrafishbytalenmediatedsomaticinactivationoftheretinoblastoma1tumorsuppressorrb1 AT woolardkevind rapidtumorinductioninzebrafishbytalenmediatedsomaticinactivationoftheretinoblastoma1tumorsuppressorrb1 AT essnerjeffreyj rapidtumorinductioninzebrafishbytalenmediatedsomaticinactivationoftheretinoblastoma1tumorsuppressorrb1 AT mcgrailmaura rapidtumorinductioninzebrafishbytalenmediatedsomaticinactivationoftheretinoblastoma1tumorsuppressorrb1 |