The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity
The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity
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DOI：
10.1523/jneurosci.2423-15.2016
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发表时间：
2016-04-13
影响因子：
5.3
通讯作者：
Petruska, Jeffrey C.
中科院分区：
文献类型：
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作者：
Harrison, Benjamin J.;Venkat, Gayathri;Petruska, Jeffrey C.
未受伤神经元完整轴突的生长（通常称为侧枝出芽）有助于成人神经系统的适应性和病理可塑性，但控制这种生长的细胞内因素在很大程度上是未知的。对大鼠体内未受损伤的侧支萌芽皮区模型的感觉神经元中调节的基因进行自动功能分析，鉴定出接头蛋白 CD2 相关蛋白（CD2AP；人 CMS）是轴突生长的正调节因子。在非神经元细胞中，CD2AP 与其他衔接蛋白一样，具有选择性控制传递细胞内信号的多蛋白复合物的空间/时间组装的功能。尽管 CD2AP 多态性与迟发性阿尔茨海默病的风险增加有关，但其在轴突生长中的作用尚不清楚。体外神经突乔木结构的评估揭示了 CD2AP 过度表达和 siRNA 介导的敲低，根据 CD2AP 表达水平调节 (1) 神经突长度、(2) 神经突复杂性和 (3) 生长锥丝状伪足数量。我们首次证明 CD2AP 与 NGF 受体 TrkA 和 PI3K 调节亚基 p85 形成新型多蛋白复合物，TrkA: p85 关联程度受 CD2AP 水平正向调节。 CD2AP 还通过 AKT（而非 ERK）调节 NGF 信号传导，并通过 TrkA(+)/RAB5(+) 信号内体调节长程信号传导。神经元中的 CD2AP mRNA 和蛋白质水平在侧支萌芽期间增加，但在损伤后下降，这表明，虽然通常一起考虑，但这两个成人轴突生长过程是根本不同的。这些数据将 CD2AP 定位为主要的细胞内信号分子，协调 NGF 信号传导以调节完整成体轴突的侧枝发芽和结构可塑性。
Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth. In non-neuronal cells, CD2AP, like other adaptor proteins, functions to selectively control the spatial/temporal assembly of multiprotein complexes that transmit intracellular signals. Although CD2AP polymorphisms are associated with increased risk of late-onset Alzheimer's disease, its role in axon growth is unknown. Assessments of neurite arbor structure in vitro revealed CD2AP overexpression, and siRNA-mediated knockdown, modulated (1) neurite length, (2) neurite complexity, and (3) growth cone filopodia number, in accordance with CD2AP expression levels. We show, for the first time, that CD2AP forms a novel multiprotein complex with the NGF receptor TrkA and the PI3K regulatory subunit p85, with the degree of TrkA: p85 association positively regulated by CD2AP levels. CD2AP also regulates NGF signaling through AKT, but not ERK, and regulates long-range signaling though TrkA(+)/RAB5(+) signaling endosomes. CD2AP mRNA and protein levels were increased in neurons during collateral sprouting but decreased following injury, suggesting that, although typically considered together, these two adult axonal growth processes are fundamentally different. These data position CD2AP as a major intracellular signaling molecule coordinating NGF signaling to regulate collateral sprouting and structural plasticity of intact adult axons.