Transcription factor expression and notch-dependent regulation of neural progenitors in the adult rat spinal cord
Transcription factor expression and notch-dependent regulation of neural progenitors in the adult rat spinal cord
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DOI：
10.1523/jneurosci.21-24-09814.2001
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发表时间：
2001-12-15
影响因子：
5.3
通讯作者：
Nakafuku, M
中科院分区：
文献类型：
--
作者：
Yamamoto, S;Nagao, M;Nakafuku, M
最近的研究表明，神经干细胞和其他祖细胞存在于成人中枢神经系统。然而，对其性质的细节仍然知之甚少。本文从分子水平研究了成年大鼠脊髓神经前体细胞的特性及其调控机制。成人和胚胎祖细胞通常表达各种同源异型（Pax 6，Pax 7，Nkx2.2和Prox 1）和碱性螺旋-环-螺旋（bHLH）型（Ngn 2，Mash 1，NeuroD 1和Olig 2）转录调控因子在体外。然而，与它们的胚胎对应物不同，成年祖细胞不能产生表达适合于脊髓运动神经元或中间神经元的标记物的特定神经元，包括Islet 1，Lim 1，Lim 3和HB 9。表达同源结构域因子Pax 6、Pax 7和Nkx2.2的细胞也在体内对损伤作出反应，并以独特的模式分布在受损的脊髓中。然而，无论是表达的神经原性bHLH因子，包括Ngn 2，Mash 1，NeuroD 1，也没有随后产生的新的神经元，可以检测到在损伤的组织。我们的研究结果表明，通过细胞表面受体Notch的信号参与了这种限制。Notch 1在体内的表达在对损伤的响应中增强。此外，Notch信号在体外的激活抑制了成体祖细胞的分化，而Notch信号的衰减和Ngn 2的强制表达显著增强了神经发生。这些结果表明，成人祖细胞的内在特性和局部环境信号，包括Notch信号，占成人脊髓的再生潜力有限。
Recent studies have demonstrated that neural stem cells and other progenitors are present in the adult CNS. Details of their properties, however, remain poorly understood. Here we examined the properties and control mechanisms of neural progenitors in the adult rat spinal cord at the molecular level. Adult and embryonic progenitors commonly expressed various homeodomain-type (Pax6, Pax7, Nkx2.2, and Prox1) and basic helix-loop-helix (bHLH)-type (Ngn2, Mash1, NeuroD1, and Olig2) transcriptional regulatory factors in vitro. Unlike their embryonic counterparts, however, adult progenitors could not generate specific neurons that expressed markers appropriate for spinal motoneurons or interneurons, including Islet1, Lim1, Lim3, and HB9. Cells expressing the homeodomain factors Pax6, Pax7, and Nkx2.2 also emerged in vivo in response to injury and were distributed in unique patterns in the lesioned spinal cord. However, neither the expression of the neurogenic bHLH factors including Ngn2, Mash1, and NeuroD1 nor subsequent generation of new neurons could be detected in injured tissue. Our results suggest that signaling through the cell-surface receptor Notch is involved in this restriction. The expression of Notch1 in vivo was enhanced in response to injury. Furthermore, activation of Notch signaling in vitro inhibited differentiation of adult progenitors, whereas attenuation of Notch signals and forced expression of Ngn2 significantly enhanced neurogenesis. These results suggest that both the intrinsic properties of adult progenitors and local environmental signals, including Notch signaling, account for the limited regenerative potential of the adult spinal cord.