Cytoskeletal mechanisms of dendrite arbor shape development

摘要 亚型特异性树突状结构的特化和动态修饰不仅决定了 不同类别的神经元与其他神经元形成功能连接，但也直接影响亚型， 特定的计算属性。树突状的形式，并通过扩展功能，主要是介导的亚细胞 细胞骨架成分的组织和动力学。因此，识别分子因子和细胞因子， 调节亚型特异性树突状细胞发生的过程对于我们理解 在健康和神经病理学中，细胞骨架组织与神经元形式和功能之间的联系。 蛋白质稳态，或蛋白质稳态，是必不可少的细胞健康和作为一个监视系统， 神经毒性聚集体涉及许多神经退行性疾病状态。尽管如此重要， 相对较少的是已知的正常发育作用的蛋白质稳态调节途径， 驱动树突多样性或亚型特异性细胞骨架组织。我们在上一个供资周期的工作 为结合神经遗传学操作、体内时空多通道 用于亚型的多通道和时变神经元重建的成像和计算技术 特定的树突状细胞骨架结构。这一策略产生了新的见解，局部细胞骨架控制 调节树状乔木多样性的机制，不能单独预测或定量 其特征在于没有这些方法的协同作用。对于下一个融资周期，我们假设 进化上保守的PP 2A磷酸酶和TRiC/CCT伴侣蛋白复合物起着重要的作用， 对细胞骨架的时空组织和动力学施加控制的蛋白质稳态调节剂 组成部分潜在的亚型特定的树突乔木多样性。为了研究这个核心假设，我们 提出以下紧密相连的目标。首先，我们将阐明PP 2A的机制作用 磷酸酶和TRiC/CCT伴侣蛋白复合物在指导亚型特异性树突状分支中的作用。第二、 我们将确定PP 2A和TRiC/CCT的功能要求和假定的分子靶点， 亚型特异性树突细胞骨架结构和动力学。第三，我们将进行计算研究 树突状形态和时空细胞骨架分布，直接整合和协同 前两个目标，从而产生一个闭环研究系统。这些研究不仅 揭示了驱动细胞骨架组织和动力学的新分子机制， 不同树突乔木的出现，而且还开发和传播神经信息学工具和数据 对神经科学界有着广泛的影响。

Abstract The specification and dynamic modification of subtype specific dendritic architecture not only dictates how distinct classes of neurons form functional connections with other neurons, but also directly influences subtype- specific computational properties. Dendritic form, and by extension function, is chiefly mediated by subcellular organization and dynamics of cytoskeletal components. Thus, identifying molecular factors and cellular processes that regulate subtype specific dendritogenesis is essential to our understanding of the mechanistic links between cytoskeletal organization and neuronal form and function in both health and neuropathologies. Protein homeostasis, or proteostasis, is essential to cellular health and as a surveillance system against neurotoxic aggregates implicated in numerous neurodegenerative disease states. Despite this importance, relatively little is known regarding the normal developmental roles of proteostasis regulatory pathways in driving dendritic diversity or subtype-specific cytoskeletal organization. Our work in the previous funding cycle provided the foundations for combining neurogenetic manipulations, in vivo spatio-temporal multichannel imaging and computational techniques for multichannel and time-varying neuronal reconstructions of subtype specific dendritic cytoskeletal architectures. This strategy yielded novel insights into local cytoskeletal control mechanisms regulating dendritic arbor diversity that could not have been solely predicted or quantitatively characterized without the synergy of these approaches. For this next funding cycle, we hypothesize that the evolutionarily conserved PP2A phosphatase and TRiC/CCT chaperonin complexes function as essential proteostasis regulators that exert control over the spatiotemporal organization and dynamics of cytoskeletal components underlying subtype-specific dendritic arbor diversity. To investigate this core hypothesis, we propose the following tightly linked aims. First, we will elucidate the mechanistic role(s) of the PP2A phosphatase and TRiC/CCT chaperonin complex in directing subtype specific dendritic arborization. Second, we will identify the functional requirements and putative molecular targets of PP2A and TRiC/CCT in regulating subtype specific dendritic cytoskeletal architecture and dynamics. Third, we will conduct computational studies of dendritic morphology and spatio-temporal cytoskeletal distributions that directly integrates and synergizes with the first two aims thereby generating a closed-loop investigational system. These studies will not only reveal novel molecular mechanisms driving cytoskeletal organization and dynamics that functionally contribute to the emergence of diverse dendritic arbors, but also develop and disseminate neuroinformatic tools and data of broad impact to the neuroscience community.