Regulation of dendritic spine shape and synapse and dendrite stability by Arg

Arg 对树突棘形状和突触以及树突稳定性的调节

基本信息

  • 批准号:
    8266050
  • 负责人:
  • 金额:
    $ 1.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-02-01 至 2013-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Neural circuits do not develop properly in neurodevelopmental disorders and degrade prematurely in neurodegenerative disorders. We have shown that dendritic spine morphogenesis and later synapse and dendrite stability requires the Abl-related gene (Arg) nonreceptor tyrosine kinase, which acts downstream of integrin adhesion receptors to mediate changes in cytoskeletal structure. We seek to understand how integrins signal through Arg and its effectors to control the formation and maintenance of neural circuitry. Our first aim is to elucidate the roles for Arg in dendritic spine morphology, synapse stability, and dendrite maintenance. Dendrites and synapses develop normally through postnatal day 21 in the arg-/- mouse cortex and hippocampus, but dendritic spines do not mature properly, leading to synapse and dendrite loss and behavioral deficits by postnatal day 42. We will use electrophysiology and analyze three-dimensional reconstructions of synapses and dendrites in arg-/- mice to examine how the loss of Arg-signaling pathways compromises the formation, stability, and function of synapses and dendrites. We will also use a conditionally inactivatable arg allele and an inducible arg transgene to determine when Arg signaling is required for proper synapse development and to protect against synapse loss and dendritic degeneration. Our second aim is to understand how integrins activate Arg to regulate synapse and dendrite stability. Our work has shown that integrins act through Arg to mediate changes in cytoskeletal structure, but we do not understand how Arg is recruited to integrin heterodimers to achieve kinase activation in vivo. We will test the hypothesis, supported by preliminary data, that integrin 21 or 23 cytoplasmic tails bind directly to Arg to mediate kinase activation. Integrins containing 21 or 23 subunits regulate synapse formation and dendrite stability in vivo, but it is unclear which specific integrin heterodimers act through Arg to regulate synapse and dendrite maintenance. We will monitor Arg signaling pathways and analyze synapse and dendrite structure in integrin 21 and 23 mutant mice to determine which integrins act through Arg to control dendritic spine morphogenesis and synapse/dendrite stability. Our third aim is to determine how Arg signals through its effectors to regulate synapse and dendrite stability. Arg is required for proper dendritic spine morphogenesis in vivo, but we do not understand how Arg coordinates the cytoskeletal changes required for these processes. Our biochemical studies have identified several substrates (p190RhoGAP, cortactin, myosin IIB) through which Arg acts to promote changes in cytoskeletal structure. We will examine how integrin signaling through Arg affects the distribution of these Arg substrates in cultured cortical neurons. We will also test whether RNAi knockdown of the substrates affects dendritic spine structure and synapse and dendrite stability in established hippocampal neuronal cultures. PUBLIC HEALTH RELEVANCE: Neural circuits do not develop properly in neurodevelopmental disorders, such as mental retardation, and degrade prematurely in neurodegenerative disorders, such as Alzheimer's Disease. Defects in synapse function and/or reductions in synapse number lead to the loss of dendrite segments and degeneration of neural circuits. We will study a biochemical pathway that regulates synapse morphogenesis and function and protects against degeneration of neural circuits in the brain.
描述(由申请方提供):神经回路在神经发育障碍中不能正常发育,在神经退行性疾病中过早降解。我们已经表明,树突棘形态发生和后来的突触和树突的稳定性,需要与神经元相关的基因(精氨酸)非受体酪氨酸激酶,其作用下游的整合素粘附受体介导的细胞骨架结构的变化。我们试图了解整合素如何通过精氨酸及其效应子信号来控制神经回路的形成和维持。我们的第一个目标是阐明精氨酸在树突棘形态,突触稳定性和树突维持中的作用。树突和突触在出生后第21天在arg-/-小鼠皮层和海马中正常发育,但树突棘未正常成熟,导致出生后第42天突触和树突丢失和行为缺陷。我们将使用电生理学和分析的三维重建的突触和树突在Arg-/-小鼠研究Arg信号通路的损失如何影响突触和树突的形成,稳定性和功能。我们还将使用条件失活的arg等位基因和诱导型arg转基因来确定何时需要Arg信号传导来进行适当的突触发育,并防止突触丢失和树突状细胞变性。我们的第二个目标是了解整合素如何激活精氨酸调节突触和树突的稳定性。我们的工作表明,整合素通过精氨酸介导细胞骨架结构的变化,但我们不知道如何招募精氨酸整合素异源二聚体,以实现在体内激酶激活。我们将测试的假设,支持的初步数据,即整合素21或23细胞质尾直接结合精氨酸介导激酶激活。整合素含有21或23个亚基调节突触的形成和树突的稳定性在体内,但目前还不清楚具体的整合素异二聚体通过精氨酸调节突触和树突的维护。我们将监测Arg信号通路,并分析整合素21和23突变小鼠的突触和树突结构,以确定哪些整合素通过Arg控制树突棘形态发生和突触/树突稳定性。我们的第三个目标是确定精氨酸信号如何通过其效应调节突触和树突的稳定性。精氨酸是必要的适当的树突棘形态发生在体内,但我们不明白精氨酸如何协调这些过程所需的细胞骨架的变化。我们的生化研究已经确定了几种底物(p190 RhoGAP,corneum,肌球蛋白IIB),通过精氨酸的作用,以促进细胞骨架结构的变化。我们将研究如何整合素信号通过精氨酸影响这些精氨酸底物在培养的皮层神经元的分布。我们还将测试RNAi敲除底物是否影响已建立的海马神经元培养物中的树突棘结构以及突触和树突稳定性。公共卫生相关性:神经回路在神经发育障碍(如智力迟钝)中不能正常发育,并且在神经退行性疾病(如阿尔茨海默病)中过早退化。突触功能的缺陷和/或突触数量的减少导致树突节段的丢失和神经回路的退化。我们将研究调节突触形态发生和功能的生化途径,并防止大脑神经回路的退化。

项目成果

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Anthony J Koleske其他文献

Anthony J Koleske的其他文献

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{{ truncateString('Anthony J Koleske', 18)}}的其他基金

Dysregulation of TRIO GEF1 activity in neurodevelopmental disorders
TRIO GEF1 活性在神经发育障碍中的失调
  • 批准号:
    10714793
  • 财政年份:
    2023
  • 资助金额:
    $ 1.2万
  • 项目类别:
Direct binding and control of microtubule elongation by Abl2
Abl2 直接结合并控制微管伸长
  • 批准号:
    9978453
  • 财政年份:
    2020
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of Dendritic Spine Stability via Regulation of a Stable Actin Pool
通过稳定肌动蛋白库的调节控制树突棘稳定性
  • 批准号:
    10373463
  • 财政年份:
    2018
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of Dendritic Spine Stability via Regulation of a Stable Actin Pool
通过稳定肌动蛋白库的调节控制树突棘稳定性
  • 批准号:
    10590119
  • 财政年份:
    2018
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of Dendritic Spine Stability via Regulation of a Stable Actin Pool
通过稳定肌动蛋白库的调节控制树突棘稳定性
  • 批准号:
    10365989
  • 财政年份:
    2018
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of Dendritic Spine Stability via Regulation of a Stable Actin Pool
通过稳定肌动蛋白库的调节控制树突棘稳定性
  • 批准号:
    10115123
  • 财政年份:
    2018
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of Dendritic Spine Stability via Regulation of a Stable Actin Pool
通过稳定肌动蛋白库的调节控制树突棘稳定性
  • 批准号:
    9895869
  • 财政年份:
    2018
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of actin dynamics and dendritic spine stability by Arg and cortactin
Arg 和 cortactin 控制肌动蛋白动力学和树突棘稳定性
  • 批准号:
    8883739
  • 财政年份:
    2014
  • 资助金额:
    $ 1.2万
  • 项目类别:
Control of actin dynamics and dendritic spine stability by Arg and cortactin
Arg 和 cortactin 控制肌动蛋白动力学和树突棘稳定性
  • 批准号:
    8791215
  • 财政年份:
    2014
  • 资助金额:
    $ 1.2万
  • 项目类别:
Regulation of invadopodia formation in breast cancer cells
乳腺癌细胞侵袭伪足形成的调节
  • 批准号:
    7847676
  • 财政年份:
    2009
  • 资助金额:
    $ 1.2万
  • 项目类别:

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