Transsynaptic coordination of synaptic growth, function, and stability by the L1-type CAM Neuroglian.
Transsynaptic coordination of synaptic growth, function, and stability by the L1-type CAM Neuroglian.
复制标题
DOI：
10.1371/journal.pbio.1001537
复制
发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Pielage J
中科院分区：
文献类型：
--
作者：
Enneking EM;Kudumala SR;Moreno E;Stephan R;Boerner J;Godenschwege TA;Pielage J
外周和中枢突触的实验揭示了L1型CAM神经胶质细胞能够跨突触控制突触发育和维持的调节机制。突触连接的精确控制对于神经元回路的发育和功能至关重要。虽然在我们理解细胞粘附分子如何介导轴突引导和突触形成方面取得了重大进展，但体内控制突触维持或可塑性的机制仍然很大程度上未被表征。在无偏见的RNAi筛选中，我们确定了果蝇L1型CAM神经胶质细胞（Nrg）作为突触生长，功能和稳定性的中央协调员。我们证明了细胞外Ig结构域和细胞内锚定相互作用基序对突触的发育和稳定性是必不可少的。Nrg在体内与锚蛋白2结合，并且降低与锚蛋白2的结合亲和力的突变导致运动神经元中Nrg移动性的增加。然后，我们证明了Nrg-Ank 2相互作用控制着神经肌肉接头处突触生长和稳定性的平衡。相反，在中央突触，突触前和突触后Nrg的跨突触相互作用需要动态的，时间和空间的，调节细胞内锚定结合基序，以协调突触前和突触后的发展。我们的研究在两个互补的模型突触确定的L1型CAM和锚蛋白之间的相互作用的调节作为一个重要的新模块，使本地控制的突触连接和功能，同时保持一般的神经元电路架构。神经元回路的功能依赖于精确的连接，学习和记忆等过程涉及通过选择性形成和消除突触来改善这种连接。在突触接触处直接介导细胞-细胞相互作用的细胞粘附分子（CAM）被认为介导这种结构性突触可塑性。在这项研究中，我们使用了一个公正的遗传筛选，以确定果蝇L1型CAM神经胶质细胞作为突触形成和维护的中央调节器。我们表明，细胞内锚蛋白相互作用的基序，连接神经胶质细胞的细胞骨架，是一个重要的监管网站的神经胶质细胞的流动性，粘附和突触功能。在运动神经元中，锚蛋白结合的强度直接控制突触形成和维持之间的平衡。然而，在中央突触，需要神经胶质细胞-锚蛋白相互作用的动态调节来协调跨突触发育。我们的研究确定了L1型CAM与锚蛋白的相互作用，作为一种新的调节模块，能够在不改变一般神经元回路结构的情况下局部和精确地控制突触连接。这种相互作用与正常的神经系统发育和疾病有关，因为L1型CAM的突变会导致人类的智力迟钝和精神疾病。
Experiments in peripheral and central synapses reveal the regulatory mechanisms that enable trans-synaptic control of synapse development and maintenance by the L1-type CAM Neuroglian. The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg–Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture. The function of neuronal circuits relies on precise connectivity, and processes like learning and memory involve refining this connectivity through the selective formation and elimination of synapses. Cell adhesion molecules (CAMs) that directly mediate cell–cell interactions at synaptic contacts are thought to mediate this structural synaptic plasticity. In this study, we used an unbiased genetic screen to identify the Drosophila L1-type CAM Neuroglian as a central regulator of synapse formation and maintenance. We show that the intracellular Ankyrin interaction motif, which links Neuroglian to the cytoskeleton, is an essential regulatory site for Neuroglian mobility, adhesion, and synaptic function. In motoneurons, the strength of Ankyrin binding directly controls the balance between synapse formation and maintenance. At a central synapse, however, a dynamic regulation of the Neuroglian–Ankyrin interaction is required to coordinate transsynaptic development. Our study identifies the interaction of the L1-type CAM with Ankyrin as a novel regulatory module enabling local and precise control of synaptic connectivity without altering general neuronal circuit architecture. This interaction is relevant for normal nervous system development and disease as mutations in L1-type CAMs cause mental retardation and psychiatric diseases in humans.
登录
查看更多内容
DOI：
10.1083/jcb.137.3.703
发表时间：
1997-05-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Garver TD;Ren Q;Tuvia S;Bennett V
通讯作者：
Bennett V
影响因子：
64.8
作者：
Cavey, Matthieu;Rauzi, Matteo;Lecuit, Thomas
通讯作者：
Lecuit, Thomas
影响因子：
25
作者：
Godenschwege, TA;Hu, HL;Murphey, RK
通讯作者：
Murphey, RK
影响因子：
16.2
作者：
Bednarek, Ewa;Caroni, Pico
通讯作者：
Caroni, Pico
影响因子：
3.7
作者：
Guan, Hanjun;Maness, Patricia F.
通讯作者：
Maness, Patricia F.