Molecular control of neurogenesis in the adult subventricular zone

 描述(申请人提供)：成年哺乳动物大脑中的神经干细胞(NSCs)已被证明在大脑高级功能的可塑性以及脑损伤后的修复和再生中发挥重要作用。然而，我们对成体神经干细胞在分子水平的调控的了解仍然很粗略，这也是为什么利用内源性神经干细胞进行脑修复的策略尚未取得足够的临床应用进展的原因之一。本研究的目的是以小鼠为模型系统，通过确定成年神经干细胞的关键调控机制来填补目前的知识空白。特别是，我们最近的研究表明，同源结构域转录因子(Tf)Gsx2和碱性螺旋-环-螺旋Tf-Ascl1在成人脑室下区(SVZ)的神经干细胞控制中起着至关重要的作用，它们在胚胎脑发育中起着重要的作用。重要的是，我们发现Gsx2和Ascl1控制着神经干细胞中成人特有的调控步骤。我们还表明，这些因子在损伤诱导的神经发生中发挥着重要作用。我们的初步研究进一步表明，与胚胎中Gsx2和Ascl1以线性级联方式(Gsx2、Ascl1)作用不同，它们的交叉抑制在控制成年NSCs命运方面发挥了关键作用。基于这些新的发现和活体工具，我们将检验Gsx2和Ascl1及其下游效应器在完整和损伤条件下以成人特有的方式控制神经干细胞的关键作用的假设。 在以下三个具体目标中：目标1将通过对Gsx2、Ascl1及其下游靶点的研究，揭示成年NSCs谱系进展的新机制。目的2将通过对Gsx2及其下游因子调控的研究，揭示神经干细胞的区域性指定和嗅球(OB)中间神经元神经元亚型指定的新机制。目的3将通过研究Gsx2的表达和作用，揭示损伤诱导神经发生的新机制。

 DESCRIPTION (provided by applicant): Neural stem cells (NSCs) in the adult mammalian brain have been demonstrated to play important roles in the plasticity of higher brain function and repair and regeneration after brain damage. Yet, our understanding of the regulation of adult NSCs at the molecular level remains sketchy, and this is one of the reasons for why strategies to harness the capacity of endogenous NSCs for brain repair have not yet made sufficient progress for clinical applications. The goal of this study is to fill in this current knowledge gap by identifying crucial regulatory mechanisms in adult NSCs using mouse as a model system. In particular, our recent studies have shown that the homeodomain transcription factor (TF) Gsx2 and basic helix-loop-helix TF Ascl1, which have been well known for their essential roles in embryonic brain development, play vital roles in controlling NSCs in the adult subventricular zone (SVZ). Importantly, we found that Gsx2 and Ascl1 control adult-specific regulatory steps in NSCs. We also have shown that these TFs play essential roles in injury-induced neurogenesis. Our preliminary studies further suggest that unlike in embryos in which Gsx2 and Ascl1 act in a linear cascade (Gsx2 ¿ Ascl1 ¿ neurogenesis), their cross-inhibition plays a key role in controlling the fate of adult NSCs. Based on these novel findings and in vivo tools, we will test the hypothesis that Gsx2 and Ascl1, as well as their downstream effectors, play crucial roles in controlling NSCs in adult-specific manners under intact and injury conditions in the following three specific aims: Aim 1 will reveal novel mechanisms for lineage progression of adult NSCs through studies on Gsx2, Ascl1, and their downstream targets. ; Aim 2 will reveal novel mechanisms for regional specification of NSCs and neuronal subtype specification of olfactory bulb (OB) interneurons through studies on the regulation of Gsx2 and its downstream factors.; Aim 3 will reveal novel mechanisms for injury-induced neurogenesis through studies on the regulation of the expression and action of Gsx2.