Role of Ankyrin-B in the Nervous System

锚蛋白-B 在神经系统中的作用

• 批准号: 10351323
• 负责人: Damaris N Lorenzo
• 金额: $ 6.43万
• 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: 2020-01-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351323
• 关键词: ANK2 gene; ASD patient; 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; parent grant; postnatal period; postsynaptic; receptor; synaptic function; synaptic pruning; synaptogenesis; trafficking; transmission process; white matter

SUMMARY (parent grant) 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.

摘要（家长资助） 发育中和成人中枢神经系统（CNS）中功能神经元网络的建立 需要适当的轴突规格、生长、分支、定位和突触发生。未能适当 在发育过程中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，或神经退行性疾病和精神疾病。从头 编码锚蛋白 B (AnkB) 的 ANK2 突变已在自闭症谱系障碍 (ASD) 中被发现 患者，其中一些表现出轴突发育异常。小鼠 AnkB 亚型的神经元丢失导致 中枢神经系统中缺乏长轴突投射，轴突长度整体减少，证实 AnkB 在人类和小鼠的神经元发育中发挥重要作用。 AnkB 有两种主要亚型 脑;普遍表达 220kDa (AnkB220) 和神经元特异性 440kDa AnkB (AnkB440)。我们最近 发现 AnkB220 具有运动性，可促进培养神经元中基于微管的轴突运输 促进轴突生长。相比之下，AnkB440 与参与轴突引导的细胞粘附分子相互作用 和突触发生。缺乏 AnkB440 的神经元会增加轴突分支和突触发生。我们也 发现 AnkB 在谷氨酸能突触的突触后密度处富集。不同的表型 小鼠体内的异构体特异性敲除凸显了 AnkB220 和 AnkB440 的特殊功能。因此，有 需要揭示神经元 AnkB 的功能作用并辨别其 AnkB220 的细胞特化 和 AnkB440 亚型。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 揭示神经元发育和连接缺陷背后的精确细胞机制 由于这些异构体的丢失。我们的研究构成了一项新颖的努力来检验我们的中心假设：AnkB 通过组合和特定的作用来协调神经元的结构和功能连接 AnkB220 和 AnkB440 亚型。为了实现我们的目标，我们的目标是：（1）确定 AnkB220 驱动的轴突是否 体内长程中枢神经系统轴突的发育和维持需要运输； (2) 定义分子 AnkB440 介导的大脑发育过程中突触连接调节所需的相互作用；和 (3)定义AnkB在突触后的作用。我们的研究将直接有助于我们对 轴突生长和突触发生的基本机制，从而了解轴突生长和突触发生的病理生理学 锚蛋白相关的神经系统疾病和其他与白质和突触缺陷相关的脑部疾病 连接性。