Cargando…
A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()()
Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma u...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735629/ https://www.ncbi.nlm.nih.gov/pubmed/26806352 http://dx.doi.org/10.1016/j.neo.2015.12.002 |
_version_ | 1782413112953012224 |
---|---|
author | Misuraca, Katherine L. Hu, Guo Barton, Kelly L. Chung, Alexander Becher, Oren J. |
author_facet | Misuraca, Katherine L. Hu, Guo Barton, Kelly L. Chung, Alexander Becher, Oren J. |
author_sort | Misuraca, Katherine L. |
collection | PubMed |
description | Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3 +/Nestin +/Sox2 + population lining the fourth ventricle and a Pax3 +/NeuN + parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53(fl/fl) mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67 +, Nestin +, Olig2 +, and largely GFAP − and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease. |
format | Online Article Text |
id | pubmed-4735629 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-47356292016-02-29 A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() Misuraca, Katherine L. Hu, Guo Barton, Kelly L. Chung, Alexander Becher, Oren J. Neoplasia Article Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3 +/Nestin +/Sox2 + population lining the fourth ventricle and a Pax3 +/NeuN + parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53(fl/fl) mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67 +, Nestin +, Olig2 +, and largely GFAP − and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease. Neoplasia Press 2016-01-21 /pmc/articles/PMC4735629/ /pubmed/26806352 http://dx.doi.org/10.1016/j.neo.2015.12.002 Text en © 2015 Institut National de la Santé Et de la Recherche Médicale http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Misuraca, Katherine L. Hu, Guo Barton, Kelly L. Chung, Alexander Becher, Oren J. A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() |
title | A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() |
title_full | A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() |
title_fullStr | A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() |
title_full_unstemmed | A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() |
title_short | A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells()() |
title_sort | novel mouse model of diffuse intrinsic pontine glioma initiated in pax3-expressing cells()() |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735629/ https://www.ncbi.nlm.nih.gov/pubmed/26806352 http://dx.doi.org/10.1016/j.neo.2015.12.002 |
work_keys_str_mv | AT misuracakatherinel anovelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT huguo anovelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT bartonkellyl anovelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT chungalexander anovelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT becherorenj anovelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT misuracakatherinel novelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT huguo novelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT bartonkellyl novelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT chungalexander novelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells AT becherorenj novelmousemodelofdiffuseintrinsicpontinegliomainitiatedinpax3expressingcells |