Neurodevelopmental disorder-associated Rho regulators in neocortical development

新皮质发育中神经发育障碍相关的 Rho 调节因子

• 批准号: 10339420
• 负责人: Linda Van Aelst
• 金额: $ 58.6万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339420
• 关键词: Address; Adolescent; Adult; Affect; Animals; Axon; Behavior; Behavioral; Binding; Biochemical; Birth; Birth Place; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Cell physiology; Cognition Disorders; Cues; Data; Defect; Dendrites; Destinations; Development; Developmental Delay Disorders; Disease; Electrophysiology (science); Electroporation; Embryo; Embryonic Development; Epilepsy; Exhibits; Genetic; Genetic Epistasis; Goals; Human; Impairment; Individual; Intellectual functioning disability; Knowledge; Label; Lead; Learning Disabilities; Light; Link; Mediating; Membrane; Mental Retardation; Methods; Molecular; Morphogenesis; Morphology; Mus; Mutation; Neocortex; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Newborn Infant; Pathogenesis; Pathway interactions; Patients; Play; Positioning Attribute; Predisposition; Process; Proline-Rich Domain; Proteins; Radial; Regulation; Role; Seizures; Sensory; Signal Transduction; Structure; Synapses; Syndrome; Techniques; Testing; Tyrosine Phosphorylation; associated symptom; base; behavioral response; experimental study; fiber cell; genetic approach; hippocampal pyramidal neuron; in utero; in vivo; innovation; insight; migration; mutant; neocortical; novel; novel therapeutic intervention; postnatal; receptor; recruit; rho; rho GTPase-activating protein; social; tool

ABSTRACT Proper development and function of the neocortex, a brain structure critical for all higher-order functions, relies on the tightly controlled migration of neocortical pyramidal (NP) neurons from their place of birth to their final position in the developing neocortex. Once neurons reach their destination, they further mature and establish functional connections. Significantly, defects in the migration of NP neurons are linked to neurodevelopmental disorders (NDDs) of cognition and epilepsy, highlighting the importance of this process in neocortical development and function. Yet, the molecular mechanisms that govern NP neuron migration and associated brain disorders remain poorly understood. We recently uncovered that the multi-domain containing Rho-GAP oligophrenin-1 (OPHN1) is prominently expressed in NP neurons in the developing neocortex, and, importantly, that it plays a key role in the proper migration and consequent positioning of newborn NP neurons in vivo. Notably, mutations in OPHN1 cause a syndromic form of intellectual disability. Besides learning disabilities, affected individuals typically exhibit epileptic seizures and behavioral/sensory deficits. These findings provide a unique entry point for studying the mechanisms that control NP neuron migration and how such deregulation contributes to common brain disorders. This application aims to define the underlying mechanisms by which OPHN1 governs NP neuron migration, to elucidate how OPHN1 is regulated in such neurons, and to characterize how its loss during embryonic development affects the cytoarchitecture/function of the postnatal/adult mouse neocortex and the behavior of such animals. To this end, Aim 1 will define and characterize the cellular processes and effector pathways OPHN1 impinges on. Our preliminary data suggest that OPHN1 exerts its effects via RhoA-dependent and RhoA-independent pathways, each influencing distinct cellular aspects of NP neuron migration. Therefore, we will delineate the RhoA effector pathway(s) involved and identify novel molecular interactions that mediate OPHN1’s effects on NP neuron migration, using innovative genetic, molecular and cellular tools. Aim 2 will investigate the mechanisms that regulate OPHN1 function in NP neurons, with a particular focus on the BDNF receptor tyrosine kinase TrkB, which we posit to act as key regulator of OPHN1 in NP neuron migration by phosphorylating and consequently activating the protein. To test this, we will employ molecular/cellular tools and genetic strategies to illuminate the mode of OPHN1 regulation by BDNF/TrkB signaling and address its functional importance for NP neuron migration. Aim 3 will apply morphometric and electrophysiological techniques to examine the morphology of NP neurons and neuronal/network activity in neocortices of juvenile/adult NEX- Ophn1cKO mice lacking OPHN1 in postmitotic NP neurons. Furthermore, we will examine the behavior of NEX- Ophn1cKO mice, with a particular focus on sensory-based and social/behavioral responses in addition to seizure susceptibility. Together, our studies will provide novel insight into the mechanisms governing NP neuron migration and shed light on the pathomechanisms contributing to NDDs of cognition and epilepsy.

抽象的 新皮层的适当发展和功能是所有高阶功能至关重要的大脑结构 在新皮层锥体（NP）神经元的紧密控制的迁移中 在发育中的新皮层中的位置。一旦神经元到达目的地，他们就会进一步成熟并建立 功能连接。值得注意的是，NP神经元迁移的缺陷与神经发育有关 认知和癫痫的疾病（NDD），强调了这一过程在新皮层中的重要性 发展和功能。然而，控制NP神经元迁移和相关的分子机制 脑部疾病仍然了解不足。我们最近发现了包含Rho-gap的多域 寡素1（OPHN1）在发育中的新皮层中的NP神经元中显着表达，重要的是 它在适当的迁移以及随之而来的新生儿NP神经元在体内的定位中起着关键作用。尤其， OPHN1中的突变会导致智力障碍的综合征形式。除了学习障碍，受影响 个体通常表现出癫痫发作和行为/感觉不足。这些发现提供了独特的 研究控制NP神经元迁移的机制以及这种放松管制如何贡献的切入点 常见的脑疾病。该应用程序旨在定义OPHN1管理的基本机制 NP神经元迁移，以阐明在此类神经元中如何调节OPHN1的方式，并表征其损失 在胚胎发育过程中，会影响产后/成年小鼠新皮层的细胞结构/功能 这样的动物的行为。为此，AIM 1将定义和表征细胞过程和效应器 ophn1撞击路径。我们的初步数据表明，OPHN1通过Rhoa依赖性执行其效果 和与RhoA无关的途径，每个途径都会影响NP神经元迁移的不同细胞方面。所以， 我们将描绘涉及的Rhoa效应途径并确定介导的新分子相互作用 OPHN1使用创新的遗传，分子和细胞工具对NP神经元迁移的影响。 AIM 2意志 研究调节NP神经元中OPHN1功能的机制，特别关注BDNF 受体酪氨酸激酶TRKB，我们呈阳性作为NP神经元迁移中OPHN1的关键调节剂 磷酸化并因此激活蛋白质。为了测试这一点，我们将采用分子/细胞工具和 通过BDNF/TRKB信号传导阐明OPHN1调控模式的遗传策略并解决其功能 对于NP神经元迁移的重要性。 AIM 3将对形态计量学和电生理技术应用于 检查NP神经元和神经元/网络活性的形态 ophn1cko小鼠缺乏有丝分裂后NP神经元中缺乏OPHN1的小鼠。此外，我们将研究nex-的行为 OPHN1CKO小鼠，除了癫痫发作外，特别关注基于感官的社会/行为反应 敏感性。我们的研究将共同​​提供有关NP神经元的机制的新颖洞察力 迁移并阐明了导致认知和癫痫病NDD的病理机制。