The role of endocytic L1 trafficking in polarized adhesion and migration of nerve growth cones
The role of endocytic L1 trafficking in polarized adhesion and migration of nerve growth cones
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DOI：
10.1523/jneurosci.21-23-09194.2001
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发表时间：
2001-12-01
影响因子：
5.3
通讯作者：
Yoshihara, F
中科院分区：
文献类型：
--
作者：
Kamiguchi, H;Yoshihara, F
神经生长锥的运动高度依赖于其与细胞粘附分子（CAM）介导的微环境的动态相互作用。这些粘附相互作用可以通过改变生长锥上CAM的密度和亲合力在空间上进行调节。以前的研究表明，L1，CAM的免疫球蛋白超家族的成员，是内吞在生长锥的中央域，然后离心囊泡运输和重新插入到质膜的前缘。本文主要研究体外培养背根神经节神经元内吞L1运输的功能意义。我们表明，L1为基础的神经突生长的速度有一个正相关的生长锥中的内吞L1的量，而刺激神经突生长通过N-钙粘蛋白依赖的机制不增加L1的内吞。在L1基底上迁移的生长锥表现出L1介导的粘附的陡峭梯度（在生长锥的前缘处的强粘附和在中心域处的弱粘附）。在生长锥中通过细胞内加载针对α-适配蛋白（网格蛋白相关AP-2适配子的亚基）的功能阻断抗体抑制L1内吞作用后，L1粘附的这种梯度减弱。该抗体对L1内吞作用的抑制也降低了L1依赖性生长锥迁移的速率。这些结果表明，生长锥积极易位CAM创建空间不对称的粘合剂与环境的相互作用，这种空间不对称性是重要的生长锥迁移。
Motility of the nerve growth cone is highly dependent on its dynamic interactions with the microenvironment mediated by cell adhesion molecules (CAMs). These adhesive interactions can be spatially regulated by changing the density and avidity of CAMs on the growth cone. Previous studies have shown that L1, a member of the immunoglobulin superfamily of CAMs, is endocytosed at the central domain of the growth cone followed by centrifugal vesicular transport and reinsertion into the plasma membrane of the leading edge. The present paper focuses on the functional significance of endocytic L1 trafficking in dorsal root ganglia neurons in vitro. We demonstrate that the rate of L1-based neurite growth has a positive correlation with the amount of endocytosed L1 in the growth cone, whereas stimulation of neurite growth via an N-cadherin-dependent mechanism does not increase L1 endocytosis. A growth cone that migrates on an L1 substrate exhibits a steep gradient of L1-mediated adhesion (strong adhesion at the growth cone's leading edge and weak adhesion at the central domain). This gradient of L1 adhesion is attenuated after inhibition of L1 endocytosis in the growth cone by intracellular loading of a function-blocking antibody against alpha -adaptin, a subunit of the clathrin-associated AP-2 adaptor. Inhibition of L1 endocytosis by this antibody also decreased the rate of L1-dependent growth cone migration. These results indicate that the growth cone actively translocates CAMs to create spatial asymmetry in adhesive interactions with its environment and that this spatial asymmetry is important for growth cone migration.