The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation
The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation
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DOI：
10.1101/gad.560310
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发表时间：
2010-04-01
影响因子：
10.5
通讯作者：
Schuetz, Guenther
中科院分区：
文献类型：
--
作者：
Liu, Hai-Kun;Wang, Ying;Schuetz, Guenther
恶性胶质瘤是最常见的原发性脑肿瘤，并且与对治疗的频繁抵抗以及不良预后相关。在这里，我们证明，核受体无尾（Tlx），这在成人中只表达在星形胶质细胞样B细胞的脑室下区，作为一个关键的调节器的神经干细胞（NSC）的扩展和脑肿瘤的起始从NSC。Tlx的过表达拮抗小鼠中神经干细胞的年龄依赖性衰竭，并导致干/祖细胞从其天然生态位迁移。随着年龄的增长，神经干细胞的增加持续存在，并导致老年脑组织中新生神经元的有效产生。这些细胞启动神经胶质瘤样病变和神经胶质瘤的发展。胶质瘤的发展在肿瘤抑制基因p53缺失后加速。Tlx诱导的NSC扩增和胶质瘤发生与血管生成增加相关，这允许脑肿瘤干细胞在血管周围小生境中的迁移和维持。我们还表明，TLX转录过表达的人原发性胶质母细胞瘤中，TLX的表达仅限于巢蛋白阳性血管周围肿瘤细胞的亚群。我们的研究清楚地表明了神经干细胞如何促进干细胞特异性转录因子驱动的脑肿瘤发生，从而为原发性脑肿瘤的组织发生和分子发病机制提供了新的见解。
Malignant gliomas are the most common primary brain tumors, and are associated with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient production of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are associated with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-positive perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorgenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and molecular pathogenesis of primary brain tumors.