Translational Regulation of Adult Neural Stem Cells

描述(申请人提供)：出生后和成人大脑中的神经干细胞(NSCs)可能在正常的大脑功能(如学习和记忆)以及大脑对损伤和疾病的反应中发挥重要作用。了解神经干细胞和成人神经发生不仅是神经干细胞治疗应用的关键，也是许多其他类型干细胞治疗应用的关键。此外，神经干细胞为研究神经发育和与出生后病因相关的疾病(如自闭症谱系障碍)提供了一个很好的模型系统。我们的最终目标是揭示神经干细胞的调控机制，并发现治疗精神障碍的新靶点。神经发生被定义为新神经元的产生和成熟。尽管成人神经发生的具体目的还不完全清楚，但我们和其他人的工作已经提供了证据，支持它在成人神经可塑性和海马体依赖学习中的重要作用。成年海马区的神经发生和学习在许多病理条件下都会发生改变。然而，它们如何导致人类智力残疾--一种学习和记忆方面的缺陷--仍不清楚。脆性X智力低下蛋白(FMRP)是一种富含神经元的选择性RNA结合蛋白，与多聚核糖体相关，调节蛋白质翻译。FMRP的功能丧失会导致脆性X综合征，这是遗传性智能障碍和自闭症最常见的单基因形式，并伴有学习障碍。尽管进行了广泛的努力，但脆性X综合征学习缺陷的潜在机制仍不清楚。在目前的资助期间，我们发现FMRP在成年NSCs中高度表达，并调节NSC命运指定中涉及的几种蛋白质的翻译。使用零和条件诱导小鼠遗传学，我们已经证明FMRP缺乏损害海马神经发生和海马体依赖学习(PLOS Genet 2010；NAT Med 2011)。此外，操纵FMRP调节的通路，如GSK3抑制剂的治疗，可以挽救FMRP缺失小鼠的神经发生和学习缺陷(Hum Mol Genet 2011)。这些数据为FMRP在出生后神经发生和学习中的作用提供了直接的证据，并为我们理解RNA结合蛋白介导的翻译调控在出生后/成人神经发生和学习障碍中的特定角色和功能影响提供了独特的机会。基于这些令人兴奋的数据和我们的实力，目前的提议旨在测试FMRP调节成人神经发生的多个阶段，其缺陷会扰乱新神经元的发育并损害新神经元功能的假设。为了验证这一假设，我们将定义FMRP在成年DG干细胞和祖细胞中的作用(目标1)；确定FMRP在新的DG神经元中的特定功能(目标2)；并确定FMRP调控成人神经发生的机制(目标3)。这些数据将不仅提供关于FMRP在神经发生中的功能的关键信息，而且还提供关于特定阶段的神经发生在学习和记忆中的功能的关键信息。

DESCRIPTION (provided by applicant): Neural stem/progenitor cells (NSCs) in postnatal and adult brains may play a major role in both normal brain functions, such as learning and memory, as well as the brain's response to injury and disease. Understanding NSCs and adult neurogenesis holds the key to therapeutic applications of not only NSCs but also many other types of stem cells. In addition, NSCs make an excellent model system for studying neurodevelopment and related disorders with postnatal etiology, such as autism spectrum disorders. Our ultimate goal is to reveal mechanisms regulating NSCs and uncover new therapeutic targets for treating mental disorders. Neurogenesis is defined as generation and maturation of new neurons. Although the specific purpose of adult neurogenesis is not entirely clear, work from ours and others' have provided evidence supporting its important roles in adult neuroplasticity and hippocampus-dependent learning. Both adult hippocampal neurogenesis and learning are altered in a number of pathological conditions. However how they contribute to human intellectual disability, a deficiency in learning and memory, is still unclear. Fragile X mental retardation protein (FMRP) is a neuron- enriched selective RNA-binding protein associated with polyribosomes and it is known to regulate protein translation. Functional loss of FMRP leads to Fragile X syndrome, most common monogenetic form of inherited intellectual disability and autism, with learning disability. Despite extensive effort, the mechanisms underlying the learning deficits in Fragile X syndrome remain unclear. During the current funding period, we have found that FMRP is highly expressed in adult NSCs and regulates the translational of several proteins involved in NSC fate specification. Using null and conditional inducible mouse genetics, we have demonstrated that FMRP deficiency impairs both hippocampal neurogenesis and hippocampus-dependent learning (PloS Genet 2010; Nat Med 2011). In addition, manipulation of FMRP-regulated pathways, such as treatment by a Gsk3¿ inhibitor, rescues both neurogenesis and learning deficits of FMRP null mice (Hum Mol Genet 2011). These data provide direct evidence for the role of FMRP in postnatal neurogenesis and learning and present us a unique opportunity for understanding the specific roles and functional impact of RNA binding protein- mediated translational regulation in postnatal/adult neurogenesis and learning disabilities. Built upon these exciting data and our strength, the current proposal aims to test the hypothesis that FMRP regulates multiple stages of adult neurogenesis and its deficiency disrupts the development and impairs the function of new neurons. To test this hypothesis, we will define the roles of FMRP in stem and progenitor cells in the adult DG (Aim 1); determine specific function of FMRP in new DG neurons (Aim 2); and determine the mechanism underlying FMRP regulation of adult neurogenesis (Aim 3). These data will provide critical information regarding not only the function of FMRP in neurogenesis but also the function of stage-specific neurogenesis in learning and memory.