The Nuclear Receptor TLX Is Required for Gliomagenesis within the Adult Neurogenic Niche
The Nuclear Receptor TLX Is Required for Gliomagenesis within the Adult Neurogenic Niche
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DOI：
10.1128/mcb.01122-12
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发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Zhang, Chun-Li
中科院分区：
文献类型：
--
作者：
Zou, Yuhua;Niu, Wenze;Zhang, Chun-Li
神经干细胞（NSC）在成人大脑中不断产生功能性神经元。由于其增殖能力，失调的 NSC 或其祖细胞已被提议作为许多原发性中枢神经系统肿瘤（包括浸润性神经胶质瘤）的起源细胞。孤儿核受体 TLX 是成体 NSC 增殖所必需的，其上调可促进脑肿瘤形成。然而，目前尚不清楚 TLX 是否是胶质瘤发生所必需的。我们使用小鼠模型研究了 TLX 和几种肿瘤抑制因子之间的遗传相互作用，以及 TLX 依赖性 NSC 在神经胶质瘤发生过程中的作用。在这里，我们表明，TLX 对于 p21、p53 或 Pten 的单个删除或 Pten 和 p53 的联合删除的成体 NSC 的增殖至关重要。虽然 Tlx 突变小鼠中仍然会形成脑肿瘤，但这些肿瘤的浸润性较低，并且很少与成年神经源性微环境相关，表明其非干细胞起源。总而言之，这些结果表明 TLX 在 NSC 依赖性神经胶质瘤发生中发挥关键作用，并暗示 TLX 作为抑制 NSC 衍生脑肿瘤发展的治疗靶点。
Neural stem cells (NSCs) continually generate functional neurons in the adult brain. Due to their ability to proliferate, deregulated NSCs or their progenitors have been proposed as the cells of origin for a number of primary central nervous system neoplasms, including infiltrating gliomas. The orphan nuclear receptor TLX is required for proliferation of adult NSCs, and its upregulation promotes brain tumor formation. However, it is unknown whether TLX is required for gliomagenesis. We examined the genetic interactions between TLX and several tumor suppressors, as well as the role of TLX-dependent NSCs during gliomagenesis, using mouse models. Here, we show that TLX is essential for the proliferation of adult NSCs with a single deletion of p21, p53, or Pten or combined deletion of Pten and p53. While brain tumors still form in Tlx mutant mice, these tumors are less infiltrative and rarely associate with the adult neurogenic niches, suggesting a non-stem-cell origin. Taken together, these results indicate a critical role for TLX in NSC-dependent gliomagenesis and implicate TLX as a therapeutic target to inhibit the development of NSC-derived brain tumors.