Cargando…
BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma
Medulloblastomas are the most common malignant pediatric brain tumor and have been divided into four major molecular subgroups. Animal models that mimic the principal molecular aberrations of these subgroups will be important tools for preclinical studies and allow greater understanding of medullobl...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911170/ https://www.ncbi.nlm.nih.gov/pubmed/27310018 http://dx.doi.org/10.1371/journal.pone.0156907 |
_version_ | 1782438100025212928 |
---|---|
author | Shackleford, Gregory M. Shi, Xiang-He Swanson, Kimberly S. Mahdi, Min Y. Gonzalez-Gomez, Ignacio Asgharzadeh, Shahab D’Apuzzo, Massimo Erdreich-Epstein, Anat Moats, Rex A. |
author_facet | Shackleford, Gregory M. Shi, Xiang-He Swanson, Kimberly S. Mahdi, Min Y. Gonzalez-Gomez, Ignacio Asgharzadeh, Shahab D’Apuzzo, Massimo Erdreich-Epstein, Anat Moats, Rex A. |
author_sort | Shackleford, Gregory M. |
collection | PubMed |
description | Medulloblastomas are the most common malignant pediatric brain tumor and have been divided into four major molecular subgroups. Animal models that mimic the principal molecular aberrations of these subgroups will be important tools for preclinical studies and allow greater understanding of medulloblastoma biology. We report a new transgenic model of medulloblastoma that possesses a unique combination of desirable characteristics including, among others, the ability to incorporate multiple and variable genes of choice and to produce bioluminescent tumors from a limited number of somatic cells within a normal cellular environment. This model, termed BarTeL, utilizes a Barhl1 homeobox gene promoter to target expression of a bicistronic transgene encoding both the avian retroviral receptor TVA and an eGFP-Luciferase fusion protein to neonatal cerebellar granule neuron precursor (cGNP) cells, which are cells of origin for the sonic hedgehog (SHH) subgroup of human medulloblastomas. The Barhl1 promoter-driven transgene is expressed strongly in mammalian cGNPs and weakly or not at all in mature granule neurons. We efficiently induced bioluminescent medulloblastomas expressing eGFP-luciferase in BarTeL mice by infection of a limited number of somatic cGNPs with avian retroviral vectors encoding the active N-terminal fragment of SHH and a stabilized MYCN mutant. Detection and quantification of the increasing bioluminescence of growing tumors in young BarTeL mice was facilitated by the declining bioluminescence of their uninfected maturing cGNPs. Inclusion of eGFP in the transgene allowed enriched sorting of cGNPs from neonatal cerebella. Use of a single bicistronic avian vector simultaneously expressing both Shh and Mycn oncogenes increased the medulloblastoma incidence and aggressiveness compared to mixed virus infections. Bioluminescent tumors could also be produced by ex vivo transduction of neonatal BarTeL cerebellar cells by avian retroviruses and subsequent implantation into nontransgenic cerebella. Thus, BarTeL mice provide a versatile model with opportunities for use in medulloblastoma biology and therapeutics. |
format | Online Article Text |
id | pubmed-4911170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49111702016-07-06 BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma Shackleford, Gregory M. Shi, Xiang-He Swanson, Kimberly S. Mahdi, Min Y. Gonzalez-Gomez, Ignacio Asgharzadeh, Shahab D’Apuzzo, Massimo Erdreich-Epstein, Anat Moats, Rex A. PLoS One Research Article Medulloblastomas are the most common malignant pediatric brain tumor and have been divided into four major molecular subgroups. Animal models that mimic the principal molecular aberrations of these subgroups will be important tools for preclinical studies and allow greater understanding of medulloblastoma biology. We report a new transgenic model of medulloblastoma that possesses a unique combination of desirable characteristics including, among others, the ability to incorporate multiple and variable genes of choice and to produce bioluminescent tumors from a limited number of somatic cells within a normal cellular environment. This model, termed BarTeL, utilizes a Barhl1 homeobox gene promoter to target expression of a bicistronic transgene encoding both the avian retroviral receptor TVA and an eGFP-Luciferase fusion protein to neonatal cerebellar granule neuron precursor (cGNP) cells, which are cells of origin for the sonic hedgehog (SHH) subgroup of human medulloblastomas. The Barhl1 promoter-driven transgene is expressed strongly in mammalian cGNPs and weakly or not at all in mature granule neurons. We efficiently induced bioluminescent medulloblastomas expressing eGFP-luciferase in BarTeL mice by infection of a limited number of somatic cGNPs with avian retroviral vectors encoding the active N-terminal fragment of SHH and a stabilized MYCN mutant. Detection and quantification of the increasing bioluminescence of growing tumors in young BarTeL mice was facilitated by the declining bioluminescence of their uninfected maturing cGNPs. Inclusion of eGFP in the transgene allowed enriched sorting of cGNPs from neonatal cerebella. Use of a single bicistronic avian vector simultaneously expressing both Shh and Mycn oncogenes increased the medulloblastoma incidence and aggressiveness compared to mixed virus infections. Bioluminescent tumors could also be produced by ex vivo transduction of neonatal BarTeL cerebellar cells by avian retroviruses and subsequent implantation into nontransgenic cerebella. Thus, BarTeL mice provide a versatile model with opportunities for use in medulloblastoma biology and therapeutics. Public Library of Science 2016-06-16 /pmc/articles/PMC4911170/ /pubmed/27310018 http://dx.doi.org/10.1371/journal.pone.0156907 Text en © 2016 Shackleford et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Shackleford, Gregory M. Shi, Xiang-He Swanson, Kimberly S. Mahdi, Min Y. Gonzalez-Gomez, Ignacio Asgharzadeh, Shahab D’Apuzzo, Massimo Erdreich-Epstein, Anat Moats, Rex A. BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma |
title | BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma |
title_full | BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma |
title_fullStr | BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma |
title_full_unstemmed | BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma |
title_short | BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma |
title_sort | bartel, a genetically versatile, bioluminescent and granule neuron precursor-targeted mouse model for medulloblastoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911170/ https://www.ncbi.nlm.nih.gov/pubmed/27310018 http://dx.doi.org/10.1371/journal.pone.0156907 |
work_keys_str_mv | AT shacklefordgregorym bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT shixianghe bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT swansonkimberlys bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT mahdiminy bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT gonzalezgomezignacio bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT asgharzadehshahab bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT dapuzzomassimo bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT erdreichepsteinanat bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma AT moatsrexa bartelageneticallyversatilebioluminescentandgranuleneuronprecursortargetedmousemodelformedulloblastoma |