Role of ankyrin-B in the nervous system

锚蛋白-B 在神经系统中的作用

• 批准号: 10162086
• 负责人: Damaris N Lorenzo
• 金额: $ 2.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162086
• 关键词: ANK2 gene; Adult; Affect; Anatomy; Ankyrins; Axon; Axonal Transport; Binding; Biochemical; Biological Assay; Brain; Brain Diseases; Brain region; Cell Adhesion Molecules; Cell physiology; Cells; Complex; Corpus Callosum; Couples; Cytoskeleton; Data; Defect; Development; Disease; Etiology; Failure; Functional disorder; Gene Delivery; Genes; Glutamates; Goals; Grant; Growth; Human; Image; Impairment; In Vitro; Knock-out; Knockout Mice; Lead; Length; Maintenance; Mediating; Membrane; Mental disorders; Metabotropic Glutamate Receptors; Microtubules; Motor; Mus; Mutation; Nervous system structure; Neural Cell Adhesion Molecule L1; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disability; Neurologic; Neurons; Parkinson Disease; Pathway Analysis; Patients; Phenotype; Play; Process; Protein Isoforms; Proteins; Regulation; Research; Resolution; Role; Schizophrenia; Semaphorin-3; Signal Transduction; Somatosensory Cortex; Spectrin; Structure; Synapses; Synaptic Transmission; Testing; Variant; Vertebral column; Vesicle; autism spectrum disorder; axon growth; axon guidance; base; cell motility; de novo mutation; density; dynactin; in utero; in vivo; morphometry; mouse model; mutant; nervous system disorder; neuron development; neuron loss; neurotransmission; novel; postnatal period; postsynaptic; receptor; synaptic function; synaptic pruning; synaptogenesis; trafficking; transmission process; white matter

Project Summary The establishment of functional neuronal networks in the developing and adult central nervous system (CNS) requires proper axonal specification, growth, branching, targeting, and synaptogenesis. Failure to appropriately interconnect brain regions during development or to refine those connections during maturation can lead to neurodevelopmental disabilities, such as autism, or to neurodegenerative and psychiatric disorders. De novo mutations in ANK2, which encodes ankyrin-B (AnkB), have been identified in autism spectrum disorder (ASD) patients, some of whom show aberrant axonal development. Neuronal loss of AnkB isoforms in mice results in absence of long axonal projections in the CNS and an overall reduction in axonal length, confirming that AnkB serves important roles in neuronal development in both humans and mice. AnkB has two major isoforms in the brain; ubiquitously expressed 220kDa (AnkB220) and neuron-specific 440kDa AnkB (AnkB440). We recently discovered that AnkB220 is motile and promotes microtubule-based axonal transport in cultured neurons to facilitate axonal growth. In contrast, AnkB440 interacts with cell adhesion molecules implicated in axon guidance and synaptogenesis. Neurons lacking AnkB440 have increased axon branching and synaptogenesis. We also found that AnkB is enriched at the postsynaptic density of glutamatergic synapses. The different phenotypes of the isoform-specific knockout in mice highlights the specialized functions of AnkB220 and AnkB440. Thus, there is a need to uncover the functional roles of neuronal AnkB and discern the cellular specialization of its AnkB220 and AnkB440 isoforms. Here, we will use novel mouse models lacking AnkB220 or AnkB440 in cortical neurons to unravel the precise cellular mechanisms underlying the neuronal development and connectivity deficits caused by the loss of these isoforms. Our research constitutes a novel effort to test our central hypothesis that AnkB coordinates neuronal structural and functional connectivity through the combined and specific roles of the AnkB220 and AnkB440 isoforms. To achieve our goals, we aim to: (1) Determine if AnkB220-driven axonal transport is required for the development and maintenance of long-range CNS axons in vivo; (2) Define molecular interactions required for AnkB440-mediated regulation of synaptic connections during brain development; and (3) Define the roles of AnkB in the postsynapse. Our studies will directly contribute to our understanding of the fundamental mechanisms of axonal growth and synaptogenesis, thereby informing the pathophysiology of ankyrin-related neurological and other brain disorders associated with deficits in white matter and synaptic connectivity.

项目摘要 在发展中心和成人中枢神经系统（CNS）中建立功能性神经元网络 需要适当的轴突规格，生长，分支，靶向和突触发生。无法适当 开发过程中的互连大脑区域或在成熟过程中完善这些连接可能会导致 神经发育障碍，例如自闭症，或神经退行性和精神疾病。从头开始 编码Ankyrin-B（ANKB）的ANK2中的突变已在自闭症谱系障碍（ASD）中鉴定 患者，其中一些患者表现出异常的轴突发育。小鼠ANKB同工型的神经元丧失导致 中枢神经系统中没有长轴突投影，轴突长度的总体降低，证实了ANKB 在人类和小鼠的神经元发展中起重要作用。 ANKB在大脑中有两个主要的同工型。普遍表达220KDA（ANKB220）和神经元特异性 440KDA ANKB（ANKB440）。我们最近发现，ANKB220是通力的，并促进了基于微管的 培养神经元中的轴突转运以促进轴突生长。相反，ANKB440与细胞粘附相互作用 与轴突引导和突触发生有关的分子。缺乏ANKB440的神经元增加了轴突 分支和突触发生。我们还发现，ANKB在谷氨酸能的突触后密度富集 突触。小鼠中同工型特异性敲除的不同表型突出了专业功能 ANKB220和ANKB440。因此，有必要发现神经元ANKB的功能作用并辨别 其ANKB220和ANKB440同工型的细胞专业化。 在这里，我们将使用在皮质神经元中缺少ANKB220或ANKB440的新型鼠标模型来揭示精确的 这些损失引起的神经元发展和连通性缺陷的基础机制 同工型。我们的研究构成了一个新的努力，以测试我们的中心假设，即ANKB协调神经元 通过ANKB220和ANKB440的结合和特定作用的结构和功能连通性 同工型。为了实现我们的目标，我们的目标是：（1）确定是否需要ANKB220驱动的轴突运输 体内远程CNS轴突的开发和维护； （2）定义所需的分子相互作用 ANKB440介导的大脑发育过程中突触连接的调节； （3）定义 aNKB在后自言自语中。我们的研究将直接有助于我们对基本的理解 轴突生长和突触发生的机制，从而告知脚踝蛋白相关的病理生理学 与白质和突触连通性缺陷相关的神经系统疾病和其他脑疾病。