Cdk5 and adult hippocampal neurogenesis

Cdk5 和成人海马神经发生

• 批准号: 7478306
• 负责人: AMELIA J EISCH
• 金额: $ 23.55万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478306
• 关键词: Ablation; Adult; Antibodies; Belief; Birth; Brain; Cell Maturation; Cells; Cellular Morphology; Cellular biology; Cues; Cyclin-Dependent Kinase 5; Cyclins; Data; Employee Strikes; Exploratory/Developmental Grant; Future; Grant; Hippocampus (Brain); Immunohistochemistry; Investigation; Knowledge; Learning; Life; Light; Mediating; Memory; Mitotic; Molecular; Morphology; Mus; Natural regeneration; Neurons; Numbers; Phenotype; Physiological; Prosencephalon; Protein Analysis; Proteins; Regulation; Research Priority; Role; Signal Transduction; Staging; Stem Cell Development; Stem cells; Structure; System; Testing; Transgenic Organisms; Viral; base; cofactor; dentate gyrus; design; injured; insight; nerve stem cell; nestin protein; neurogenesis; novel; postnatal; protein expression; relating to nervous system; repaired

DESCRIPTION (provided by applicant): Identification of novel intracellular and microenvironmental signals that influence adult neurogenesis is a major research priority. Here we provide evidence for a novel role of cyclin dependent kinase 5 (Cdk5) in adult neurogenesis. This is striking since, unlike other cyclins, Cdk5 and its cofactors p35 and p39 are enriched in post-mitotic neurons. Based on our preliminary data, we hypothesize that Cdk5 activity in the adult hippocampus regulates proliferation and maturation of adult neural precursors. To test this hypothesis, we propose three aims to be accomplished in two years. Aim 1: Define protein expression of Cdk5 and required cofactors in subgranular zone (SGZ) precursors as they mature. We have validated the use of a novel Cdk5 antibody for protein analysis, including immunohistochemistry. Guided by our preliminary data, we will define when Cdk5 protein and its required cofactors, p35 and p39, are expressed in maturing SGZ cells. Aim 2: Determine the impact of Cdk5 ablation from precursors and their progeny on neurogenesis. New pilot data with our nestin-CreERT2 mouse suggest that inducible loss of Cdk5 from SGZ precursors and their progeny is detrimental to discrete stages of adult neurogenesis. We will determine how transgenic-mediated, precursor-specific ablation of Cdk5 impacts the a) number, b) phenotype, and c) morphology of these cells as they mature into dentate gyrus neurons. We hypothesize that loss of Cdk5 from precursors and their progeny will negatively impact their differentiation but have no effect on proliferation. Aim 3: Explore the impact of Cdk5 ablation from dentate gyrus neurons on SGZ neurogenesis. We show new data that loss of Cdk5 in mature dentate gyrus neurons has profound negative effects on SGZ precursors and immature neurons. We will test the hypothesis that Cdk5 in mature neurons in the hippocampus is critical for maintaining the SGZ neurogenic niche. We will use viral-induced ablation of Cdk5 to quantify the impact of Cdk5 ablation from mature dentate gyrus neurons on the a) number and b) morphology of SGZ precursors and immature neurons. These studies will provide fundamental insight into the potential cell autonomous effects of Cdk5 on adult neural stem cell development (Aims 1, 2), and the cell non-autonomous effects of Cdk5 in mature neurons on adult hippocampal neurogenesis via alteration of the neurogenic microenvironment (Aim 3). These studies will shed much-needed light on the physiological and pathological functions of Cdk5, and potentially indicate a highly novel role for Cdk5 in regulation of adult hippocampal structure and function. Contrary to a long-held belief that the brain cannot regenerate, the adult brain is now known to give rise to new neurons throughout life. Understanding the cues that influence these adult-generated neurons is critical, as it may hold the key to understanding brain functions, like learning and memory, and may allow us to harness these new neurons for repair of the injured or addicted brain. Here we propose to explore the impact of a novel regulator, cyclin dependent kinase 5, on the birth of new neurons in the adult brain.

描述（由申请人提供）：识别影响成体神经发生的新型细胞内和微环境信号是主要的研究重点。在这里，我们提供了细胞周期蛋白依赖性激酶 5 (Cdk5) 在成人神经发生中的新作用的证据。这是惊人的，因为与其他细胞周期蛋白不同，Cdk5 及其辅助因子 p35 和 p39 在有丝分裂后神经元中富集。根据我们的初步数据，我们假设成人海马中的 Cdk5 活性调节成人神经前体细胞的增殖和成熟。为了检验这一假设，我们提出了两年内实现的三个目标。目标 1：定义颗粒下区 (SGZ) 前体成熟时 Cdk5 和所需辅因子的蛋白表达。我们已经验证了新型 Cdk5 抗体在蛋白质分析（包括免疫组织化学）中的用途。在我们的初步数据的指导下，我们将定义 Cdk5 蛋白及其所需的辅因子 p35 和 p39 在成熟 SGZ 细胞中表达的时间。目标 2：确定前体及其后代的 Cdk5 消融对神经发生的影响。我们的 nestin-CreERT2 小鼠的新试验数据表明，SGZ 前体及其后代的 Cdk5 诱导性丢失对成年神经发生的离散阶段是有害的。我们将确定转基因介导的 Cdk5 前体特异性消融如何影响这些细胞在成熟为齿状回神经元时的 a) 数量、b) 表型和 c) 形态。我们假设前体细胞及其后代中 Cdk5 的丢失将对它们的分化产生负面影响，但对增殖没有影响。目标 3：探索齿状回神经元 Cdk5 消融对 SGZ 神经发生的影响。我们的新数据表明，成熟齿状回神经元中 Cdk5 的缺失对 SGZ 前体和未成熟神经元具有深远的负面影响。我们将检验这样的假设：海马成熟神经元中的 Cdk5 对于维持 SGZ 神经源性生态位至关重要。我们将使用病毒诱导的 Cdk5 消融来量化成熟齿状回神经元的 Cdk5 消融对 SGZ 前体和未成熟神经元 a）数量和 b）形态的影响。这些研究将为 Cdk5 对成体神经干细胞发育的潜在细胞自主效应（目标 1、2）以及成熟神经元中 Cdk5 通过改变神经源性微环境对成体海马神经发生的细胞非自主效应提供基础见解。目标3）。这些研究将为 Cdk5 的生理和病理功能提供急需的线索，并可能表明 Cdk5 在调节成人海马结构和功能中具有高度新颖的作用。与人们长期以来认为大脑无法再生的观点相反，现在已知成人大脑在一生中都会产生新的神经元。了解影响这些成人生成的神经元的线索至关重要，因为它可能是理解学习和记忆等大脑功能的关键，并且可能使我们能够利用这些新的神经元来修复受伤或成瘾的大脑。在这里，我们建议探索一种新型调节剂——细胞周期蛋白依赖性激酶5——对成人大脑中新神经元诞生的影响。