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.

汇总（父母补助金） 发育和成年中枢神经系统（CNS）功能神经元网络的建立 需要适当的轴突特化、生长、分支、靶向和突触发生。未能适当 在发育过程中连接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，如自闭症，或神经变性和精神障碍。从头 编码锚蛋白B（AnkB）的ANK 2突变已在自闭症谱系障碍（ASD）中被发现。 患者，其中一些显示异常轴突发育。小鼠中AnkB同种型的神经元缺失导致 CNS中长轴突投射的缺乏和轴突长度的总体减少，证实了AnkB 在人类和小鼠的神经元发育中起重要作用。AnkB有两个主要的同种型， 脑;普遍表达的220 kDa（AnkB 220）和神经元特异性的440 kDa AnkB（AnkB 440）。我们最近 发现AnkB 220是能动的，并促进培养神经元中基于微管的轴突运输， 促进轴突生长。相反，AnkB 440与轴突导向中涉及的细胞粘附分子相互作用， 和突触发生。缺乏AnkB 440的神经元增加了轴突分支和突触发生。我们也 发现AnkB富集在突触后致密的神经元突触。不同的表型 小鼠中的同种型特异性敲除突出了AnkB 220和AnkB 440的专门功能。因此 需要揭示神经元AnkB的功能作用并辨别其AnkB 220的细胞特化 和AnkB 440同种型。在这里，我们将使用皮质神经元中缺乏AnkB 220或AnkB 440的新型小鼠模型。 为了解开神经元发育和连接缺陷引起的精确细胞机制， 这些异构体的丢失。我们的研究构成了一个新的努力，以测试我们的中心假设，AnkB 协调神经元的结构和功能的连接，通过组合和特定的作用， AnkB 220和AnkB 440同种型。为了实现我们的目标，我们的目标是：（1）确定AnkB 220驱动的轴突是否 运输是体内长距离CNS轴突发育和维持所必需的;（2）定义分子 在脑发育期间AnkB 440介导的突触连接调节所需的相互作用;以及 (3)定义AnkB在突触后的作用。我们的研究将直接有助于我们了解 轴突生长和突触发生的基本机制，从而告知的病理生理学 与白色物质和突触缺陷相关的强直相关神经和其他脑部疾病 连通性。