IGF-II and Insulin Receptors in Neural Stem Cells

神经前体一直是发育生物学家的兴趣所在。这些细胞具有 最近引起了更广泛的神经科学界的兴趣，因为他们 参与嗅觉，学习和记忆，认知能力随着年龄的增长而下降， 取代因脑损伤或疾病而死亡的神经元或神经胶质细胞。的 重要的细胞是神经干细胞（NSC）。这些细胞自然存在于 在特定的壁龛中，它们接收到维持它们在一个 原始状态迄今为止，IGF-II是干细胞的必要成分的可能性 由于IGF-II被认为是一种胎儿生长， 因子然而，IGF-II在脉络丛内高水平表达，这产生了 神经干细胞容易接近的脑脊液，因为它们直接延伸了一个过程 注入脑室内的脑脊液。而IGF-II和IGF-I都激活 IGF-1型受体（IGF-1 R），IGF-II也与胰岛素的剪接变体同种型结合 胰岛素样生长因子受体（IR-A）支持IGF-II与IGF-I的不同作用。这个问题的总体假设 IGF-II对于NSC的自我更新、维持和发展至关重要， 胰岛素受体。我们的总体假设将使用诱导型Cre驱动系进行测试， 实现IGF-II或胰岛素受体的时间离散缺失。将进行研究 在分子、细胞和行为层面上。确定IGF-II是维持NSC所必需的 将是一个重大的科学进步此外，确定哪个信令 受体和下游转录因子被这个信号激活， 深入了解新的策略来放大这些重要的细胞，以促进大脑生长， 在整个生命周期中的细胞替换，并增强患病或受损细胞的细胞替换 个脑袋IGF-II也在其他有成体干细胞的器官中表达，但IGF-II在成体干细胞中起作用。 IGF-II在成体干细胞维持中尚未在哺乳动物组织中探索。因此，我们认为， 在完成了所提议的实验之后，我们将处于独特的地位，可以提交R 01 调查这些重要而及时的问题。

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.