Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain
Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain
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DOI：
10.1101/gad.1743709
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发表时间：
2009-03-01
影响因子：
10.5
通讯作者：
Temple, Sally
中科院分区：
文献类型：
--
作者：
Fasano, Christopher A.;Phoenix, Timothy N.;Temple, Sally
神经干细胞（NSC）在两个前脑区域持续存在：脑室下区（SVZ）和海马。为什么前脑神经干细胞比其他区域的神经干细胞更广泛地自我更新仍不清楚。先前的研究表明，多梳因子Bmi-1是NSC自我更新所必需的，并且它抑制细胞周期抑制剂p16、p19和p21。在这里，我们表明，Bmi-1的过度表达增强自我更新的前脑神经干细胞显着超过那些来自脊髓，表现出区域差异的反应。我们发现，前脑神经干细胞需要前脑特异性转录因子Foxg 1 Bmi-1依赖的自我更新，而p21的抑制是这种相互作用的焦点。Bmi-1增强神经干细胞自我更新是显着更大的年龄和通过。重要的是，当Bmi-1在培养的成人前脑神经干细胞中过表达时，它们急剧扩增，甚至在多次传代后继续产生神经元，而对照神经干细胞仅限于神经胶质分化。这些发现共同证明了Bmi-1和Foxg 1合作对维持NSC多能性和自我更新的重要性，并建立了一种用于在神经原性生态位之外离体产生丰富的前脑神经元的有用方法。
Neural stem cells (NSCs) persist throughout life in two forebrain areas: the subventricular zone (SVZ) and the hippocampus. Why forebrain NSCs self-renew more extensively than those from other regions remains unclear. Prior studies have shown that the polycomb factor Bmi-1 is necessary for NSC self-renewal and that it represses the cell cycle inhibitors p16, p19, and p21. Here we show that overexpression of Bmi-1 enhances self-renewal of forebrain NSCs significantly more than those derived from spinal cord, demonstrating a regional difference in responsiveness. We show that forebrain NSCs require the forebrain-specific transcription factor Foxg1 for Bmi-1-dependent self-renewal, and that repression of p21 is a focus of this interaction. Bmi-1 enhancement of NSC self-renewal is significantly greater with increasing age and passage. Importantly, when Bmi-1 is overexpressed in cultured adult forebrain NSCs, they expand dramatically and continue to make neurons even after multiple passages, when control NSCs have become restricted to glial differentiation. Together these findings demonstrate the importance of Bmi-1 and Foxg1 cooperation to maintenance of NSC multipotency and self-renewal, and establish a useful method for generating abundant forebrain neurons ex vivo, outside the neurogenic niche.