Cdk5 and adult hippocampal neurogenesis

Cdk5 和成人海马神经发生

• 批准号: 7587351
• 负责人: AMELIA J EISCH
• 金额: $ 19.63万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587351
• 关键词: Ablation; Adult; Antibodies; Belief; Birth; Brain; Cell Maturation; Cells; Cellular Morphology; 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; Phenotype; Physiological; Prosencephalon; Protein Analysis; Proteins; Regulation; Research Priority; Role; Signal Transduction; Staging; Stem Cell Development; Structure; System; Testing; Transgenic Organisms; Viral; adult neurogenesis; base; cofactor; dentate gyrus; design; injured; insight; nerve stem cell; nestin protein; neurogenesis; novel; postnatal; protein expression; repaired; stem cell biology

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）：鉴定影响成人神经发生的新型细胞内和微环境信号是主要的研究优先级。在这里，我们为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提供了证据。这是令人惊讶的，因为与其他细胞周期蛋白不同，CDK5及其辅因子p35和p39富含有丝分裂后神经元。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的增殖和成熟。为了检验这一假设，我们提出三个目标要在两年内完成。 AIM 1：定义CDK5的蛋白质​​表达，并在成熟时在亚颗粒区（SGZ）前体中所需的辅助因子。我们已经验证了新型CDK5抗体用于蛋白质分析，包括免疫组织化学。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何时在成熟的SGZ细胞中表达。目标2：确定CDK5从前体及其后代对神经发生的影响。使用我们的Nestin-Creert2小鼠的新试点数据表明，SGZ前体及其后代的CDK5诱导损失对成人神经发生的离散阶段有害。我们将确定CDK5的转基因介导的前体特异性消融如何影响a）数字，b）表型和c）这些细胞成熟成齿状回神经元时的形态。我们假设从前体及其后代失去CDK5会对它们的分化产生负面影响，但对增殖没有影响。 AIM 3：探索齿状回神经元中CDK5消融对SGZ神经发生的影响。我们显示了新的数据，即成熟的齿状回神经元中CDK5的丧失对SGZ前体和未成熟神经元具有深远的负面影响。我们将检验以下假设：海马中成熟神经元中的CDK5对于维持SGZ神经源性生殖位至关重要。我们将使用病毒诱导的CDK5消融来量化CDK5从成熟的齿状回神经元对A）数量和B）SGZ前体和未成熟神经元的形态的影响进行量化。这些研究将提供对CDK5对成年神经干细胞发育的潜在细胞自主影响的基本见解（AIMS 1、2），以及通过改变神经源性微环境的成年神经元对成年神经元神经发生对成人神经元神经发生的非自治作用（目标3）。这些研究将为CDK5的生理和病理功能提供急需的启示，并有可能表明CDK5在调节成人海马结构和功能中的高度新作用。与长期以来对大脑无法再生的信念相反，现在众所周知，成年大脑会引起新的神经元。了解影响这些成年神经元的线索至关重要，因为它可能是理解大脑功能（例如学习和记忆）的关键，并且可能使我们能够利用这些新神经元来修复受伤或上瘾的大脑。在这里，我们建议探索新型调节剂细胞周期蛋白依赖性激酶5对成人大脑新神经元的诞生的影响。