Cytoskeletal mechanisms of dendrite arbor shape development

摘要 亚型特定树枝状结构的规范和动态修改不仅规定了 不同类别的神经元与其他神经元形成功能联系，但也直接影响亚型- 特定的计算属性。树突状细胞的形成和延伸功能主要由亚细胞介导 细胞骨架组件的组织和动力学。因此，识别分子因素和细胞 调节亚型特异性树突状细胞发生的过程是我们理解其机制的关键。 在健康和神经病理学中，细胞骨架组织与神经元形态和功能之间的联系。 蛋白质稳态，或蛋白质稳态，对细胞健康和作为预防疾病的监测系统至关重要。 神经毒性聚集体与许多神经退行性疾病状态有关。尽管这很重要， 对蛋白平衡调节通路的正常发育作用知之甚少。 驱动树突多样性或特定亚型的细胞骨架组织。我们在上一个资金周期中的工作 为结合神经遗传学操作提供了基础，体内时空多通道 亚型多通道时变神经元重建的成像和计算技术 特殊的树突状细胞骨架结构。这一策略对局部细胞骨架控制产生了新的见解。 调节树枝乔木多样性的机制无法单独预测或量化 没有这些方法的协同作用。对于下一个资金周期，我们假设 进化上保守的PP2A磷酸酶和TIC/CCT伴侣蛋白复合体是必不可少的 对细胞骨架的时空组织和动力学施加控制的蛋白平衡调节剂 亚型特有树状乔木多样性的基础成分。为了研究这一核心假设，我们 提出以下紧密相连的目标。首先，我们将阐明PP2A的机制作用(S) 磷酸酶和TIC/CCT伴侣蛋白复合体在指导亚型特异性树突树枝形成中的作用。第二, 我们将确定PP2A和TRIC/CCT在调控中的功能要求和可能的分子靶点 亚型特有的树突状细胞骨架结构和动力学。第三，我们将进行计算研究 树突形态和细胞骨架时空分布的直接整合和协同作用 具有前两个目的，从而产生一个闭环系统。这些研究不仅将 揭示驱动细胞骨架组织的新分子机制和功能贡献的动力学 不同树枝乔木的出现，但也开发和传播神经信息学工具和数据 对神经科学界有广泛的影响。

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.