Genetic control of neural stem cell homeostasis

项目摘要 神经系统的发育、生长和再生依赖于神经干细胞（NSC）的稳态，这是一种神经系统的状态。 NSC自我更新、分化和存活之间的微妙平衡。神经干细胞内稳态的缺陷 广泛的神经发育、精神和神经变性疾病。的分子机制 神经干细胞内稳态控制的基础仍然知之甚少。我们建议阐明基本的 利用果蝇幼虫脑II型成神经细胞研究神经干细胞内环境稳定的遗传控制机制 (NBs)做模特果蝇NBs在发现信号分子和细胞信号分子方面发挥了重要作用。 这些机制主要涉及NSC内稳态。与哺乳动物神经干细胞的谱系相似， 果蝇幼虫脑中的II型NB谱系含有过渡扩增中间祖细胞（IP），其可以 产生大量的分化后代。Notch信号传导对于维持细胞内稳态是至关重要的。 II型NB谱系。Notch信号传导的抑制导致NB不能被适当地维持，而Notch信号传导的抑制导致NB不能被适当地维持。 过度活化引起异位NB形成和脑肿瘤发生。Notch信号也调节了 哺乳动物神经干细胞的稳态，与失调的N信号已链接到脑癌。分子 然而，N信号调节NSC体内平衡的机制还不清楚。以前的研究 NSC中N信号的研究主要集中在无毛抑制因子[Su（H）]介导的典型N信号。 相关转录因子。然而，我们在上一个资助期的研究发现，一种新的非- 在胞质溶胶中操作的典型N信号传导途径也是关键性的。这个非典型的组成部分 N信号通路包括线粒体PTEN诱导的激酶1（PINK 1），雷帕霉素的机制靶点 复合物-2（mTORC 2）和mTORC 2底物AKT。这种非经典N信号通路的临床意义 我们观察到果蝇大脑中的肿瘤起始癌干细胞（CSC）样细胞 肿瘤模型和人GBM样品对该途径的干扰特别敏感。而且我们 发现这种非经典途径对线粒体氧化磷酸化发挥翻译控制作用 相关的mRNA。该提案的目标是摆脱神经干细胞转录调控的现状 通过关注新发现的N信号转导中的翻译控制机制。我们的核心假设是， 非经典N信号通过线粒体共翻译质量控制调节NSC稳态 mRNA，从而调节线粒体蛋白质组和功能。为了验证这一假设，我们提出了两个具体的 目标。目的1阐明共翻译质量控制途径如何介导Notch对神经干细胞的作用 体内平衡目的2将剖析Notch调控共翻译质量的分子机制 控制过程在成功完成这些目标后，我们将产生新的机械见解， Notch对神经干细胞稳态的调控。我们预计这将为研究开辟全新的方向 Notch在NSC生物学、癌症生物学和成人脑功能中的基本作用。

Project Summary Nervous system development, growth, and regeneration depend on neural stem cell (NSC) homeostasis, a state of delicate equilibrium between NSC self-renewal, differentiation, and survival. Defects in NSC homeostasis underlie broad neurodevelopmental, psychiatric, and neurodegenerative disorders. The molecular and cellular mechanisms underlying the control of NSC homeostasis remain poorly understood. We propose to elucidate the basic mechanisms underlying the genetic control of NSC homeostasis, using Drosophila larval brain type II neuroblasts (NBs) as a model. Drosophila NBs have been instrumental in discovering signaling molecules and cellular mechanisms that are centrally involved in NSC homeostasis. Similar to mammalian NSCs in lineage hierarchy, the type II NB lineages in the Drosophila larval brain contain transit-amplifying intermediate progenitors (IPs), which can generate a vast number of differentiated progenies. Notch signaling is critical for maintaining the homeostasis of type II NB lineages. Inhibition of Notch signaling results in NB not being properly maintained, whereas Notch hyperactivation causes ectopic NB formation and brain tumorigenesis. Notch signaling also regulates the homeostasis of mammalian NSCs, with deregulated N signaling having been linked to brain cancer. The molecular mechanisms by which N signaling regulates NSC homeostasis, however, are not well understood. Previous studies of N signaling in NSCs have focused heavily on canonical N signaling mediated by Suppressor of Hairless [Su(H)]- related transcription factors. However, our studies in the previous funding period have found that a novel non- canonical N signaling pathway operating in the cytosol is also critically involved. Components of this non-canonical N signaling pathway include mitochondrial PTEN-induced kinase 1 (PINK1), mechanistic target of rapamycin complex-2 (mTORC2), and mTORC2 substrate AKT. Clinical significance of this non-canonical N signaling pathway is underscored by our observation that tumor-initiating cancer stem cell (CSC)-like cells in both Drosophila brain tumor models and human GBM samples are particularly sensitive to perturbation of this pathway. Moreover, we found that this non-canonical pathway exerts translational control over mitochondrial oxidative phosphorylation related mRNAs. The goal of this proposal is to move away from the status quo of transcriptional regulation of NSCs by focusing on the newly discovered translational control mechanism in N signaling. Our central hypothesis is that non-canonical N signaling regulates NSC homeostasis through co-translational quality control of mitochondrial mRNAs, thus modulating mitochondrial proteome and function. To test this hypothesis, we propose two Specific Aims. Aim 1 will elucidate how the co-translational quality control pathway mediates the effect of Notch on NSC homeostasis. Aim 2 will dissect the molecular mechanism by which Notch regulates the co-translational quality control process. Upon successful completion of these Aims, we will have generated new mechanistic insights into the control of NSC homeostasis by Notch. We anticipate that this will open up entirely new directions for studying the fundamental roles of Notch in NSC biology, cancer biology, and adult brain function.