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:
  • 金额:
    $ 58.6万
  • 依托单位:
  • 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

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.
摘要 新皮层是一种对所有高级功能至关重要的大脑结构,它的正常发育和功能依赖于 新皮层锥体神经元从其出生地到其最终的迁移 在发育中的新皮层中的位置。一旦神经元到达目的地,它们进一步成熟并建立 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。 认知障碍(NDD)和癫痫,强调了这一过程在新皮质 发展和功能。然而,控制NP神经元迁移和相关的分子机制, 对脑部疾病的了解仍然很少。我们最近发现,含有Rho-GAP的多结构域 寡聚蛋白-1(OPHN 1)在发育中的新皮层的NP神经元中显著表达,并且,重要的是, 它在体内新生NP神经元的适当迁移和随后的定位中起关键作用。值得注意的是, OPHN 1的突变导致智力残疾的综合征形式。除了学习障碍, 个体通常表现出癫痫发作和行为/感觉缺陷。这些发现提供了一个独特的 研究控制NP神经元迁移的机制以及这种失调如何起作用的切入点 常见的脑部疾病此应用程序旨在定义OPHN 1管理的基本机制 NP神经元迁移,以阐明OPHN 1在这些神经元中是如何调节的,并表征其丢失的方式。 在胚胎发育期间影响出生后/成年小鼠新皮质的细胞结构/功能, 这些动物的行为。为此,目标1将定义和表征细胞过程和效应子 我们的初步数据表明,OPHN 1通过RhoA依赖性 和RhoA-独立的途径,每个影响NP神经元迁移的不同细胞方面。因此,我们认为, 我们将描述RhoA效应通路,并确定新的分子相互作用, OPHN 1对NP神经元迁移的影响,使用创新的遗传,分子和细胞工具。目标2将 研究NP神经元中OPHN 1功能的调节机制,特别关注BDNF 受体酪氨酸激酶TrkB,我们认为它是NP神经元迁移中OPHN 1的关键调节因子, 磷酸化并因此激活蛋白质。为了验证这一点,我们将使用分子/细胞工具, 通过BDNF/TrkB信号转导阐明OPHN 1调节模式并解决其功能的遗传策略 NP神经元迁移的重要性。目标3将应用形态测量和电生理技术, 检查NP神经元的形态和神经元/网络活动在青少年/成人NEX- 在有丝分裂后NP神经元中缺乏OPHN 1的Ophn 1cKO小鼠。此外,我们将研究NEX的行为- Ophn 1cKO小鼠,除癫痫发作外,还特别关注基于感觉的反应和社会/行为反应 易感性总之,我们的研究将为NP神经元的调控机制提供新的见解 迁移和阐明的病理机制,有助于认知和癫痫的NDD。

项目成果

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Linda Van Aelst其他文献

Linda Van Aelst的其他文献

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{{ truncateString('Linda Van Aelst', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 58.6万
  • 项目类别:
Molecular and cellular mechanisms governing interneuron development and connectivity
控制中间神经元发育和连接的分子和细胞机制
  • 批准号:
    9765678
  • 财政年份:
    2019
  • 资助金额:
    $ 58.6万
  • 项目类别:
Molecular and cellular mechanisms governing interneuron development and connectivity
控制中间神经元发育和连接的分子和细胞机制
  • 批准号:
    9902549
  • 财政年份:
    2019
  • 资助金额:
    $ 58.6万
  • 项目类别:
Molecular and cellular mechanisms governing interneuron development and connectivity
控制中间神经元发育和连接的分子和细胞机制
  • 批准号:
    10088479
  • 财政年份:
    2019
  • 资助金额:
    $ 58.6万
  • 项目类别:
Molecular and cellular mechanisms governing interneuron development and connectivity
控制中间神经元发育和连接的分子和细胞机制
  • 批准号:
    10334416
  • 财政年份:
    2019
  • 资助金额:
    $ 58.6万
  • 项目类别:
Molecular and cellular mechanisms governing interneuron development and connectivity
控制中间神经元发育和连接的分子和细胞机制
  • 批准号:
    10558482
  • 财政年份:
    2019
  • 资助金额:
    $ 58.6万
  • 项目类别:
The central amygdala circuits in motivated behaviors
动机行为中的中央杏仁核回路
  • 批准号:
    10543115
  • 财政年份:
    2014
  • 资助金额:
    $ 58.6万
  • 项目类别:
Rho regulator-mediated signaling in interneuron development
中间神经元发育中 Rho 调节器介导的信号传导
  • 批准号:
    8610366
  • 财政年份:
    2013
  • 资助金额:
    $ 58.6万
  • 项目类别:
Rho regulator-mediated signaling in interneuron development
中间神经元发育中 Rho 调节器介导的信号传导
  • 批准号:
    8478955
  • 财政年份:
    2013
  • 资助金额:
    $ 58.6万
  • 项目类别:
Rho regulator-mediated signaling in interneuron development
中间神经元发育中 Rho 调节器介导的信号传导
  • 批准号:
    8829348
  • 财政年份:
    2013
  • 资助金额:
    $ 58.6万
  • 项目类别:

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