Spatial and temporal regulation of synapse formation through phase separation

通过相分离调节突触形成的空间和时间

基本信息

  • 批准号:
    10445090
  • 负责人:
  • 金额:
    $ 12.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-15 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Synapses are the basic unit of neuronal communication, and consequently their location, number, and properties govern the function of neural circuits and nervous systems. How synapses form remains a fundamental question in contemporary neuroscience. A wide variety of synaptic cell adhesion molecules (syCAMs) are capable of initiating synapse formation. Downstream of these diverse connections, however, common pre- and post-synaptic specializations are formed. On the presynaptic side, an “active zone” structure is formed comprised of large multi-valent scaffolding proteins. The active zone coordinates the central functions of the presynapse by tethering and priming synaptic vesicles, clustering calcium channels, and aligning with the postsynapse through transmembrane connections. Recently the candidate showed conserved C. elegans active zone scaffolds SYD-2/Liprin-α and ELKS form liquid-liquid phase separated condensates at developing synapses, and this activity was required for active zone assembly. This work positioned active zone phase separation as a central assembly hub in the presynapse. The overall goal of the proposed studies is to determine molecular mechanisms and novel components that drive active zone phase separation, and thus presynapse formation. In Aim 1, phosphorylation will be investigated as a mechanism that controls active zone phase separation. Preliminary data suggest SAD-1 kinase phosphorylation of SYD-2 controls its activity. This phosphoregulation will be investigated with live animal in vivo imaging at single-synapse resolution in combination with in vitro phase separation assays. In Aim 2, the connection between synaptogenic syCAMs and active zone phase separation will be investigated. Multiple syCAMs have been identified to build local F- actin networks, which may link these upstream molecules to active zone phase separation. The requirement and sufficiency of F-actin networks in active zone formation and phase separation will be determined with optogenetic methods in vivo, and reconstitution of syCAM signaling and active zone phase separation in vitro. Finally, automated forward genetic screens will be performed to identify novel regulators of active zone formation. As all synapses across the diversity of neurons build a conserved core active zone, these studies have the potential to uncover common synapse assembly pathways. A fundamental understanding of synapse assembly will yield insight into synapse regeneration and future treatment of synaptopathies and is of primary relevance to the NINDS mission. The candidate will perform the K99 phase at Stanford University under the mentorship of Dr. Kang Shen, an expert in molecular and developmental neuroscience. This award will support the candidate’s career development with personalized training in research methods (genetic screening, phosphoregulation, and in vitro reconstitution) and career development (scientific writing, teaching, and management). This training will enable the candidate to successfully complete the proposed research and transition to an independent position investigating synapse formation.
突触是神经元通讯的基本单位,因此它们的位置、数量和性质决定着神经回路和神经系统的功能。突触如何形成仍然是当代神经科学的一个基本问题。多种突触细胞粘附分子(syCAM)能够启动突触形成。然而,在这些不同连接的下游,形成了共同的突触前和突触后特化。在突触前侧,形成由大的多价支架蛋白组成的“活性区”结构。活动区通过束缚和启动突触囊泡、聚集钙通道以及通过跨膜连接与突触后对齐来协调突触前的中枢功能。最近,候选人显示保守的C。elegans活性区支架SYD-2/Liprin-α和ELKS在发育中的突触处形成液-液相分离的缩合物,并且这种活性是活性区组装所必需的。这项工作将活动区相分离定位为突触前的中央组装枢纽。拟议研究的总体目标是确定驱动活动区相分离的分子机制和新组分,从而形成突触前体。在目标1中,将研究磷酸化作为控制活性区相分离的机制。初步数据表明,SAD-1激酶磷酸化SYD-2控制其活性。这种磷酸化调节将在单突触分辨率下用活动物体内成像结合体外相分离测定来研究。在目标2中,将研究突触形成syCAMs和活动区相分离之间的联系。已经鉴定了多个syCAM以构建局部F-肌动蛋白网络,其可以将这些上游分子连接到活性区相分离。F-actin网络在活性区形成和相分离中的需要和充分性将通过体内光遗传学方法和体外syCAM信号转导和活性区相分离的重建来确定。最后,将进行自动正向遗传筛选,以确定活性区形成的新调节剂。由于神经元多样性中的所有突触都建立了一个保守的核心活性区,这些研究有可能揭示共同的突触组装途径。对突触组装的基本了解将有助于深入了解突触再生和突触病变的未来治疗,并且与NINDS的使命具有主要相关性。候选人将在斯坦福大学进行K99阶段的指导下,博士康申,在分子和发育神经科学的专家。该奖项将支持候选人的职业发展与个性化的培训研究方法(遗传筛查,磷酸调节,体外重建)和职业发展(科学写作,教学和管理)。该培训将使候选人能够成功完成拟议的研究,并过渡到研究突触形成的独立职位。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Nathan McDonald其他文献

Nathan McDonald的其他文献

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{{ truncateString('Nathan McDonald', 18)}}的其他基金

Spatial and temporal regulation of synapse formation through phase separation
通过相分离调节突触形成的空间和时间
  • 批准号:
    10283421
  • 财政年份:
    2021
  • 资助金额:
    $ 12.29万
  • 项目类别:

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