Mechanisms of Local Protein Synthesis in Axon Arborization

局部蛋白质合成使亚细胞隔间具有不同的生物学功能。 神经元轴突与细胞体相距甚远。尽管数以千计的RNA存在于 轴突和功能障碍的轴突蛋白合成与多种疾病有关，我们的 对轴突局部蛋白质合成的分子机制的理解是 基本上是有限的。轴突分支在神经系统功能中起着关键作用，因为它定义了 一个适合正常突触连接的领域。我们的长期目标是阐明 管理局部蛋白质合成及其在轴突树枝形成中的作用。当前的目标 应用是获得对细胞质的作用和调节的机械性见解 多聚腺苷化元件结合蛋白(CPEB)在轴突蛋白合成和轴突树枝形成中的作用 以果蝇为模型系统。CPEB通过以下途径控制靶蛋白翻译 胞质去腺化和多腺化。我们的初步研究支持一种模型，即果蝇 CPEB、Orb2抑制唐氏综合征细胞黏附分子的蛋白质合成 (Dscam)通过胞质去烯化作用进入细胞体并介导Dscam基因的表达 转运到轴突，Wallenda/双亮氨酸拉链激酶(WND/DLK)抑制 Orb2的翻译抑制。新开发的创新方法将用于研究 以下两个目标。在目标1中，Orb2在轴突Dscam蛋白合成中的作用将是 下定决心。在目标2中，将研究WND对Orb2的调节机制。生理学 已识别的机制的作用将通过体内轴突树枝形成来确定。ORB2/CPEB为 对长期记忆的形成很重要。DSCAM与多种脑部疾病有关。 WND/DLK在多个神经元事件中起关键作用。因此，贡献将是 因为它将提供Orb2/CPEB在轴突蛋白质合成中的新作用，一种新的 WND/DLK对轴突蛋白质合成的调控及DSCAM表达和调控机制的研究 轴突的定位。预期的结果是新的分子调控机制在 轴突蛋白质合成及其在轴突树枝形成中的作用。理解分子 轴突蛋白质合成和树枝形成的机制最终将有助于形成有效的 治疗脑部疾病。

Local protein synthesis enables distinct biological functions of subcellular compartments. Neuronal axons are far apart from the cell body. Although thousands of mRNAs are present in axons and dysfunctional axonal protein synthesis is linked to multiple disorders, our understanding of the molecular mechanisms underlying the local protein synthesis in axons is largely limited. Axon arborization plays a critical role in nervous system function because it defines a territory for proper synaptic connection. The long-term goal is to elucidate the mechanisms that govern localized protein synthesis and their role in axon arborization. The objective of current application is to gain mechanistic insights on the role and the regulation of the cytoplasmic polyadenylation element binding protein (CPEB) in axonal protein synthesis and axon arborization by using Drosophila as a model system. CPEB controls target protein translation through cytoplasmic de- and poly-adenylation. Our preliminary studies support a model that a Drosophila CPEB, Orb2 suppresses the protein synthesis of Down syndrome cell adhesion molecule (Dscam) in the cell body through cytoplasmic deadenylation and mediates Dscam mRNA transport to axon where Wallenda/Dual leucine zipper kinase (Wnd/DLK) de-represses the translational suppression by Orb2. The newly developed innovative approach will be used to study the following two aims. In Aim 1, the role of Orb2 in axonal Dscam protein synthesis will be determined. In Aim 2, the regulatory mechanism of Orb2 by Wnd will be studied. The physiological role of identified mechanisms will be determined using axon arborization in vivo. Orb2/CPEB is important for long-term memory formation. Dscam is implicated in multiple brain disorders. Wnd/DLK plays a key role in multiple neuronal events. Therefore, the contribution will be significant because it will provide a novel role of Orb2/CPEB in axonal protein synthesis, a novel axonal protein synthesis regulation by Wnd/DLK, and a mechanism of Dscam expression and localization in axons. The expected outcome is the novel molecular regulatory mechanisms in axonal protein synthesis and their role in axon arborization. Understanding the molecular mechanisms of axonal protein synthesis and arborization will ultimately help developing effective treatment to brain disorders.