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 发育中和成人中枢神经系统功能神经元网络的建立 需要适当的轴突规格、生长、分支、靶向和突触发生。未能适当地 在发育过程中相互连接大脑区域或在成熟过程中完善这些连接可以导致 神经发育障碍，如自闭症，或神经退行性和精神障碍。从头开始 编码Ankyrin-B(AnkB)的ANK2基因突变已在自闭症谱系障碍(ASD)中被发现 患者，其中一些人表现出异常的轴突发育。小鼠AnkB亚型的神经元丢失导致 中枢神经系统内没有长轴突投射，轴突长度总体缩短，证实AnkB 在人类和小鼠的神经元发育中起着重要的作用。 AnkB在大脑中有两种主要的亚型：普遍表达的220 kDa(AnkB220)和神经元特异性的 440 kDa AnkB(AnkB440)。我们最近发现AnkB220具有运动性，并促进微管为基础的 培养神经元中的轴突运输以促进轴突生长。相反，AnkB440与细胞黏附相互作用 与轴突引导和突触发生有关的分子。缺乏AnkB440的神经元轴突增加 分枝和突触发生。我们还发现，AnkB在突触后的谷氨酸能密度处富含 突触。小鼠中不同的异构体特异性基因敲除的表型突出了特殊的功能 AnkB220和AnkB440。因此，有必要揭示神经元AnkB的功能作用并识别 其AnkB220和AnkB440亚型的细胞专化性。 在这里，我们将使用皮质神经元中缺乏AnkB220或AnkB440的新型小鼠模型来揭示 这些基因的缺失导致神经元发育和连接缺陷的细胞机制 异构体。我们的研究构成了一项新的努力，以检验我们的中心假设，即AnkB协调神经元 通过AnkB220和AnkB440的组合和特定作用实现结构和功能的连接 异构体。为了实现我们的目标，我们的目标是：(1)确定AnkB220驱动的轴突运输是否需要 体内长距离中枢神经系统轴突的开发和维持；(2)定义需要的分子相互作用 AnkB440介导的脑发育过程中突触连接的调节；以及(3)确定 AnkB在突触后。我们的研究将直接有助于我们对 轴突生长和突触发生的机制，从而为锚蛋白相关的病理生理提供信息 与白质和突触连接缺陷相关的神经和其他大脑疾病。