IGF-II and Insulin Receptors in Neural Stem Cells

长期以来，发育生物学家一直对神经前体感兴趣。这些细胞有 最近获得了更广泛的神经科学界的兴趣，因为他们的 参与嗅觉、学习和记忆，认知随年龄增长而下降及其潜在的 替换因脑损伤或疾病而死亡的神经元或神经胶质细胞。这个 值得关注的细胞是神经干细胞(NSCs)。这些细胞自然地存在于 在特定的小生境中，它们接收到维持它们在 原始状态。到目前为止，IGF-II是干细胞的必要组成部分的可能性 利基环境没有被考虑，很大程度上是因为IGF-II被认为是胎儿发育 因素。然而，IGF-II在脉络丛中高水平表达，从而产生 神经干细胞很容易接触到的脑脊液，因为它们直接延伸了一个过程 进入被脑脊液洗涤的脑室。而IGF-II和IGF-I都激活 胰岛素样生长因子1型受体(IGF-1R)，IGF-II也与胰岛素的剪接变体异构体结合 受体(IR-A)支持IGF-II和IGF-I的不同作用。对此的总体假设是 建议是IGF-II对于NSC的自我更新、维持和发展是必不可少的，通过 胰岛素受体。我们的总体假设将使用可诱导的CRE驱动器线进行测试，以 实现IGF-II或胰岛素受体的临时离散删除。将进行研究 在分子、细胞和行为层面。确认IGF-II是维持NSCs所必需的 作为原始细胞将是一项重大的科学进步。此外，确定哪些信令 受体和下游转录因子被这一信号激活可能很好地提供 对放大这些重要细胞以促进大脑生长的新策略的见解，保持 在疾病或受损患者的整个生命周期内进行细胞替换，并增强细胞替换 大脑。IGF-II也在其他有成体干细胞的器官中表达，但在 IGF-II在成体干细胞维持中的作用尚未在哺乳动物组织中得到探索。因此， 在完成建议的实验后，我们将独一无二地提交R01 申请调查这些重要和及时的问题。

Neural precursors have long been of interest to developmental biologists. These cells have recently gained the interest of the broader neuroscience community because of their involvement in olfaction, learning and memory, cognitive decline with aging and their potential to replace neurons or glial cells that have died as a consequence of brain injury or disease. The cells that are of significant interest are the neural stem cells (NSCs). These cells naturally reside within specific niches where they receive signals that are necessary to maintain them in a primitive state. To date, the possibility that IGF-II is a necessary component of the stem cell niche has not been considered largely because IGF-II has been regarded as a fetal growth factor. However, IGF-II is expressed at high levels within the choroid plexus, which produces the cerebrospinal fluid that is readily accessible to the NSCs because they extend a process directly into the ventricle that is bathed by cerebrospinal fluid. Whereas both IGF-II and IGF-I activate the IGF type 1 receptor (IGF-1R), IGF-II also binds to a splice variant isoform of the insulin receptor (IR-A) supporting distinct roles for IGF-II versus IGF-I. The overall hypothesis of this proposal is that IGF-II is essential for NSC self-renewal, maintenance and growth through the insulin receptor. Our overall hypothesis will be tested using inducible Cre driver lines to achieve both temporal discrete deletion of IGF-II or insulin receptors. Studies will be performed at the molecular, cellular and behavioral levels. Identifying IGF-II as necessary to sustain NSCs as primitive cells will be a significant scientific advance. Moreover, establishing which signaling receptor and downstream transcription factors are activated by this signal might well provide insights into new strategies to amplify these important cells to promote brain growth, maintain cell replacement across the lifespan and enhance cell replacement in the diseased or damaged brain. IGF-II is also expressed in other organs where there are adult stem cells, yet a role for IGF-II in adult stem cell maintenance has not been explored in mammalian tissues. Therefore, upon completing the proposed experiments we will be uniquely positioned to submit an R01 application to investigate these important and timely issues.