A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells.
A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells.
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DOI：
10.1016/j.neo.2015.12.002
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Becher OJ
中科院分区：
文献类型：
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作者：
Misuraca KL;Hu G;Barton KL;Chung A;Becher OJ
弥漫性内在脑桥神经胶质瘤（DIPG）是一种罕见的和不可治愈的脑肿瘤，主要发生在儿童和涉及脑桥，一个结构，沿着与中脑和髓质组成脑干。我们以前已经开发了脑干胶质瘤的基因工程小鼠模型，使用RCAS/Tv-a系统，通过靶向PDGF-B过表达，p53丢失，和H3.3K27M突变到Nestin表达的新生小鼠的脑干祖细胞。在这里，我们描述了一种新的小鼠模型，将这些相同的遗传改变靶向Pax 3表达细胞，其在新生小鼠脑桥中由第四脑室内衬的Pax 3 +/Nestin +/Sox 2+群体和Pax 3 +/NeuN +实质群体组成。在出生后第3天将RCAS-PDGF-B注射到Pax 3-Tv-a小鼠的脑干中导致40%的小鼠发展为无症状的低级神经胶质瘤。低级别和高级别神经胶质瘤的混合物由用RCAS-PDGF-B和RCAS-Cre注射Pax 3-Tv-a; p53 fl/fl小鼠产生，有或没有RCAS-H3. 3 K27 M。这些肿瘤是Ki 67+，Nestin +，Olig 2+，主要是GFAP-，可以在脑干内的任何地方出现，包括腹侧脑桥的经典DIPG位置。与没有突变的肿瘤相比，H3.3K27M突变的表达降低了总体H3 K27 me 3，与先前在人类和小鼠肿瘤中显示的相似。因此，我们已经产生了一种新的DIPG基因工程小鼠模型，它忠实地再现了人类疾病，并代表了一个新的平台，用于研究这种致命疾病的生物学和治疗。
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;p53fl/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.