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

基本信息

批准号：
10571903
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
项目类别：
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/10571903
关键词：
Address Adolescent Adult Affect Animals Applied Genetics 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 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 Phosphorylation 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 behavioral response experimental study fiber cell genetic approach hippocampal pyramidal neuron in utero in vivo innovation insight migration mutant neocortical novel novel therapeutic intervention postmitotic postnatal receptor recruit rho rho GTPase-activating protein social tool

项目摘要

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.

抽象的新皮质（对所有高级功能至关重要的大脑结构）的正常发育和功能依赖于新皮质锥体（NP）神经元从出生地到最终目的地的严格控制迁移一旦神经元到达目的地，它们就会进一步成熟并建立。值得注意的是，NP 神经元迁移缺陷与神经发育有关。认知障碍（NDD）和癫痫，强调了这一过程在新皮质中的重要性然而，控制 NP 神经元迁移和相关的分子机制。我们最近发现含有 Rho-GAP 的多结构域对大脑疾病仍知之甚少。 oligophrenin-1 (OPHN1) 在发育中的新皮质的 NP 神经元中显着表达，并且重要的是，它在新生 NP 神经元在体内的正确迁移和随后的定位中起着关键作用。 OPHN1 突变会导致智力障碍综合症。个体通常表现出癫痫发作和行为/感觉缺陷，这些发现提供了独特的证据。研究控制 NP 神经元迁移的机制以及这种放松管制如何发挥作用的切入点该应用旨在定义 OPHN1 控制的基本机制。 NP 神经元迁移，阐明 OPHN1 在此类神经元中的调节方式，并描述其丢失的方式在胚胎发育过程中影响出生后/成年小鼠新皮质的细胞结构/功能为此，目标 1 将定义和表征细胞过程和效应器。我们的初步数据表明 OPHN1 通过 RhoA 依赖性发挥其作用。和 RhoA 独立途径，各自影响 NP 神经元迁移的不同细胞方面。我们将描述所涉及的 RhoA 效应通路并确定介导的新型分子相互作用使用创新的遗传、分子和细胞工具 Aim 2 将了解 OPHN1 对 NP 神经元迁移的影响。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，我们认为它在 NP 神经元迁移中充当 OPHN1 的关键调节因子磷酸化并随后激活蛋白质为了测试这一点，我们将使用分子/细胞工具和阐明 BDNF/TrkB 信号传导 OPHN1 调节模式并解决其功能的遗传策略目标 3 将应用形态测量和电生理学技术来研究 NP 神经元迁移的重要性。检查青少年/成人 NEX-新皮质中 NP 神经元的形态和神经元/网络活动 Ophn1cKO 小鼠在有丝分裂后 NP 神经元中缺乏 OPHN1 此外，我们将检查 NEX- 的行为。 Ophn1cKO 小鼠，除了癫痫发作外，还特别关注基于感觉和社会/行为的反应总之，我们的研究将为控制 NP 神经元的机制提供新的见解。迁移并揭示导致认知和癫痫 NDD 的病理机制。