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Role of CLASP in neuronal morphogenesis during development

CLASP 在发育过程中神经元形态发生中的作用

基本信息

批准号：
8533033
负责人：
Fengquan Zhou
金额：
$ 33.93万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-03 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8533033
关键词：
Address Afferent Neurons Attention Axon Behavior Binding Biological Assay Brain Cell Culture Techniques Cell division Cues Cytoskeleton Dendrites Development Drosophila genus Electroporation Event Genetic Glycogen Synthase Kinase 3 Goals Growth Health In Vitro Injury Link Mediating Mediator of activation protein Mental disorders Microfilaments Microtubules Molecular Morphogenesis Mutation Natural regeneration Nerve Regeneration Nervous system structure Neurodevelopmental Disorder Neurons Pathway interactions Physiological Plus End of the Microtubule Positioning Attribute Process Property Proteins Regulation Role Side Signal Transduction Testing axon growth axon guidance base experience extracellular in utero in vivo insight migration nervous system development neural circuit neural precursor cell novel relating to nervous system repaired research study response synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Neuronal morphogenesis is a highly regulated process that ultimately depends on the remodeling of neuronal cytoskeleton in response to extracellular cues. Most previous studies of neuronal cytoskeleton focus on the regulation of actin filaments by extracellular cues. Very few studies have been done to investigate how neuronal microtubules (MTs) are regulated. Regulation of MTs is involved in every step of brain development, such as asymmetrical cell division of neural precursor cells, neuronal migration, axon growth and guidance, dendrite development, and synaptogenesis. Mutation of many MT regulating proteins during development is often associated with mental illnesses, underscoring the importance of MT regulation in normal brain development. Thus, our long-term goal is to understand how extracellular signals governing neuronal morphogenesis are transduced into MT reorganization in neurons that is necessary for proper axonal and dendritic development. Our preliminary study has revealed a novel mechanism by which MT plus end tracking proteins, CLASPs, regulate mammalian axonal and dendritic growth. We found that, unlike other +TIPs that only track MT plus ends, CLASPs display dual bindings to either the plus ends or along the sides of MTs (or MT lattices) in neurons. Functionally, we show that this unique dual MT binding behavior of CLASPs allows them to differentially regulate MT organization and axon growth in different neurons. In regenerating sensory neurons, CLASP mainly bind to MT plus ends and function to support fast axon growth. In contrast, CLASP in developing cortical neurons show increased binding along the side of MTs and act to restrict axon growth. In addition to restricting axon growth, we also provide evidence that CLASPs function to support the development of cortical neuron dendrites. Interestingly, axon guidance cue Slit also functions to repel axons and in the meantime promote dendritic growth. Because CLASP has been placed downstream of Slit to mediate axon repulsion in Drosophila, we hypothesize that CLASPs, with their unique dual MT binding property, may be converging targets of Slit-Robo signaling to regulate mammalian axonal and dendritic development. Thus, the overall goal of this study is to elucidate the role of CLASP in regulation of neuronal morphogenesis in response to extracellular cues during cortical development. To test this hypothesis, we will 1) elucidate the molecular mechanism by which CLASPs regulate MTs to control axon growth and dendritic development, 2) determine the roles of CLASPs in Slitmediated axon repulsion and dendritic growth using in vitro axon guidance assay and cell cultures, and 3) determine the in vivo roles of CLASPs in cortical neuron axon growth/guidance, and dendritic development during cortical development using in utero electroporation. This study will reveal novel molecular mechanisms by which extracellular cues regulate MTs to control neuronal morphogenesis. PUBLIC HEALTH RELEVANCE: Neuronal morphogenesis, including axon growth, guidance, and dendrite growth are key molecular events underlying the formation of the neural circuit during development, or neural repair after injuries. Mistakes in these processes during development are believed to cause many neurodevelopmental disorders. Therefore, our proposed study will not only help us understand how neural circuits form during development, but also provide valuable information of how to promote neural regeneration following injuries.

描述（由申请人提供）：神经元形态发生是一个高度调控的过程，最终取决于响应细胞外信号的神经元细胞骨架的重塑。以往对神经元细胞骨架的研究大多集中在细胞外信号对肌动蛋白丝的调控上。很少有研究调查神经元微管（MTs）是如何调节的。MTs的调控涉及大脑发育的每一步，如神经前体细胞的不对称细胞分裂、神经元迁移、轴突生长和引导、树突发育和突触发生。发育过程中许多MT调节蛋白的突变通常与精神疾病有关，这强调了MT调节在正常大脑发育中的重要性。因此，我们的长期目标是了解控制神经元形态发生的细胞外信号如何被转导为神经元中轴突和树突发育所必需的MT重组。我们的初步研究揭示了MT +末端跟踪蛋白（CLASPs）调节哺乳动物轴突和树突生长的新机制。我们发现，与其他仅跟踪MT +端的+TIPs不同，CLASPs显示与神经元中MT（或MT晶格）的正端或侧面的双重结合。在功能上，我们发现CLASPs的这种独特的双MT结合行为允许它们在不同神经元中不同地调节MT组织和轴突生长。在感觉神经元再生过程中，CLASP主要与MT +端结合，支持轴突的快速生长。相反，发育中的皮质神经元中的CLASP显示出沿mt侧增加的结合，并限制轴突的生长。除了限制轴突生长外，我们还提供证据表明CLASPs支持皮层神经元树突的发育。有趣的是，轴突引导线索Slit也起排斥轴突的作用，同时促进树突生长。由于CLASP位于果蝇的Slit下游，介导轴突排斥，我们假设具有独特双MT结合特性的CLASP可能是Slit- robo信号调节哺乳动物轴突和树突发育的会聚靶点。因此，本研究的总体目标是阐明CLASP在皮层发育过程中响应细胞外信号调控神经元形态发生中的作用。为了验证这一假设，我们将1)阐明CLASPs调节MTs控制轴突生长和树突发育的分子机制，2)利用体外轴突引导实验和细胞培养确定CLASPs在裂缝介导的轴突排斥和树突生长中的作用，以及3)利用子宫内电穿孔确定体内CLASPs在皮层神经元轴突生长/引导和皮层发育过程中树突发育中的作用。本研究将揭示细胞外信号调控MTs控制神经元形态发生的新分子机制。公共卫生相关性：神经元形态发生，包括轴突生长、引导和树突生长，是发育过程中神经回路形成或损伤后神经修复的关键分子事件。在发育过程中，这些过程中的错误被认为会导致许多神经发育障碍。因此，我们提出的研究不仅有助于我们了解神经回路在发育过程中是如何形成的，而且还为如何促进损伤后的神经再生提供了有价值的信息。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PI3K-GSK3 signalling regulates mammalian axon regeneration by inducing the expression of Smad1.

DOI：
10.1038/ncomms3690
发表时间：
2013
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Saijilafu;Hur, Eun-Mi;Liu, Chang-Mei;Jiao, Zhongxian;Xu, Wen-Lin;Zhou, Feng-Quan
通讯作者：
Zhou, Feng-Quan

Acquisition frame rate affects microtubule plus-end tracking analysis.

采集帧率影响微管加端跟踪分析。

DOI：
10.1038/nmeth.2846
发表时间：
2014
期刊：
Nature methods
影响因子：
48
作者：
Nicovich,PhilipR;Zhou,Feng-Quan
通讯作者：
Zhou,Feng-Quan

Slit2 inactivates GSK3β to signal neurite outgrowth inhibition.

DOI：
10.1371/journal.pone.0051895
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Byun J;Kim BT;Kim YT;Jiao Z;Hur EM;Zhou FQ
通讯作者：
Zhou FQ

Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration.

DOI：
10.1016/j.bbrc.2013.12.037
发表时间：
2014-01-10
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Zhang, Bo-Yin;Saijilafu;Liu, Chang-Mei;Wang, Rui-Ying;Zhu, Qingsan;Jiao, Zhongxian;Zhou, Feng-Quan
通讯作者：
Zhou, Feng-Quan

Coordinating Gene Expression and Axon Assembly to Control Axon Growth: Potential Role of GSK3 Signaling.

协调基因表达和轴突组装以控制轴突生长：GSK3信号的潜在作用。