Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans

项目摘要 突触的发育是一个高度保守的过程，它是神经功能连接的基础 系统。突触发育缺陷与多种神经疾病有关，如自闭症 谱系障碍、智力残疾、癫痫和精神分裂症。因此，恢复健康 神经发育障碍病例的突触发育是更好发育的一个目标 治疗。然而，缺乏实现这一目标的分子靶点是实现这一目标的重大障碍 开发新的治疗方法。识别促进或恢复突触发育的信号通路 将揭示调节神经元电路发育和功能的新机制。中国的总体目标是 拟议的研究旨在揭示一系列小的GTP酶是如何协调突触发育的 秀丽隐杆线虫神经肌肉接头。中心假设是PXF-1，一种Rap鸟嘌呤核苷酸 交换因子，通过顺序激活Rap、Ras和Rac促进突触发育 在神经肌肉发育过程中维持突触周围肌动蛋白细丝的GTP酶。为了鉴定分子 ，我们将使用遗传学和细胞生物学来确定 鸟嘌呤核苷酸交换因子和GTP酶激活蛋白调节细胞内的每个GTP酶 路径。我们将利用荧光生物传感器和基因工程来阐明分子机制。 通过它，Rap、RAS和RAC信号通路相互作用。拟议的研究是 创新是因为它使用了功能强大的秀丽线虫模型系统来研究GTP酶网络如何 发挥分子开关的作用，控制突触发育和马达电路功能。中国的发展和 使用新的分子工具来观察和调节体内的信号转导将提供更多的创新 用于细胞和分子神经科学。本申请中提出的研究具有重要意义，因为它们 将揭示小G蛋白信号网络如何促进突触发育以及如何调节这些 GTPase信号模块可以缓解神经元回路功能障碍。

Project Summary Synaptic development is a highly conserved process that underlies the functional connectivity of the nervous system. Deficits in synaptic development are associated with multiple neurological disorders, like autism spectrum disorders, intellectual disabilities, epilepsy, and schizophrenia. Therefore, restoration of healthy synapse development in cases of neurodevelopmental disorders represents one goal for developing better treatments. However, the lack of molecular targets to achieve this goal presents a significant barrier to the development of new therapies. Identifying the signaling pathways that promote or restore synapse development will reveal new mechanisms for modulating neuronal circuit development and function. The overall goal for the proposed research is to uncover how a series of small GTPases coordinate synapse development at the Caenorhabditis elegans neuromuscular junction. The central hypothesis is that PXF-1, a Rap guanine nucleotide exchange factor, promotes synapse development through the sequential activation of Rap, Ras, and Rac GTPases to sustain perisynaptic actin filaments during neuromuscular development. To identify the molecular mechanisms that govern the putative GTPase signaling cascade, we will use genetics and cell biology to identify the guanine nucleotide exchange factors and GTPase activating proteins that modulate each GTPase in the pathway. We will use fluorescent biosensors and genetic engineering to elucidate the molecular mechanisms through which Rap, Ras, and Rac signaling pathways interact with one another. The proposed research is innovative because it uses the powerful model system of Caenorhabditis elegans to study how GTPase networks function as molecular switches to control synapse development and motor circuit function. The development and use of new molecular tools to observe and modulate signal transduction in vivo will provide additional innovations for cellular and molecular neuroscience. The studies proposed in this application are significant because they will reveal how small G protein signaling networks promote synapse development and how modulation of these GTPase signaling modules can mitigate neuronal circuit dysfunctions.