MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo
MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo
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DOI：
10.1038/sj.neo.7900200
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发表时间：
2002-01-01
期刊：
影响因子：
4.8
通讯作者：
Holland, EC
中科院分区：
文献类型：
--
作者：
Fults, D;Pedone, C;Holland, EC
原始神经外胚层肿瘤（PNET）是小儿脑肿瘤，由控制神经祖细胞生长和分化的信号分子缺陷引起。我们使用 RCAS-TVA 系统来研究人类 PNET 中涉及的三种遗传改变对表达中间丝蛋白巢蛋白的神经祖细胞子集的生长影响。测试的遗传改变是： 1) 细胞癌蛋白 MYC 的过度表达； 2) 转录因子β-连环蛋白的激活； 3) Hedgehog受体基因Ptc的单倍体不足。 RCAS-TVA 系统使用禽类逆转录病毒载体 RCAS，将基因表达靶向转基因小鼠的特定细胞类型。为了在神经祖细胞中表达外源基因，我们使用了 Ntv-a 小鼠。在这些小鼠中，巢蛋白基因启动子驱动病毒细胞表面受体 TVA 的表达。 MYC 的异位表达（而非活化的 β-连环蛋白）促进了培养物中和体内大脑软脑膜中神经祖细胞的增殖。这些效应在具有 Ptc(+/-) 和 Ptc(+/+) 遗传背景的小鼠中同样具有渗透性。虽然 MYC 的过度表达不足以引起实质内肿瘤，但它可能通过维持未分化祖细胞的生长来促进 PNET 的形成。
Primitive neuroectodermal tumors (PNETs) are pediatric brain tumors that result from defects in signaling molecules governing the growth and differentiation of neural progenitor cells. We used the RCAS-TVA system to study the growth effects of three genetic alterations Implicated in human PNETs on a subset of neural progenitor cells that express the intermediate filament protein, nestin. The genetic alterations tested were: 1) overexpression of the cellular oncoprotein, MYC; 2) activation of transcription factor, beta-catenin; and 3) haploinsufficiency of Ptc, the hedgehog receptor gene. The RCAS-TVA system uses an avian retroviral vector, RCAS, to target gene expression to specific cell types in transgenic mice. To express exogenous genes in neural progenitor cells, we used Ntv-a mice. In these mice, the Nestin gene promoter drives expression of TVA, the cell surface receptor for the virus. Ectopic expression of MYC, but not activated beta-catenin, promoted the proliferation of neural progenitor cells in culture and in the cerebral leptomeninges in vivo. These effects were equally penetrant in mice with Ptc(+/-) and Ptc(+/+) genetic backgrounds. Although overexpression of MYC is not sufficient to cause intraparenchymal tumors, it may facilitate PNET formation by sustaining the growth of undifferentiated progenitor cells.