Department of Anatomy, Kitasato University School of Medicine , Sagamihara, Kanagawa 252-0374, Japan.
Department of Anatomy, Keio University School of Medicine , Tokyo 160-8582, Japan.
eNeuro. 2016 Aug 29;3(4). doi: 10.1523/ENEURO.0148-16.2016. eCollection 2016 Jul-Aug.
During neural development, endosomal trafficking controls cell shape and motility through the polarized transport of membrane proteins related to cell-cell and cell-extracellular matrix interactions. ADP ribosylation factor 6 (Arf6) is a critical small GTPase that regulates membrane trafficking between the plasma membrane and endosomes. We herein demonstrated that the knockdown of endogenous Arf6 in mouse cerebral cortices led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin and syntaxin12 in migrating neurons. Rescue experiments with separation-of-function Arf6 mutants identified Rab11 family-interacting protein 3 (FIP3)/Arfophilin-1, a dual effector for Arf6 and Rab11, as a downstream effector of Arf6 in migrating neurons. The knockdown of FIP3 led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin in migrating neurons, similar to that of Arf6, which could be rescued by the coexpression of wild-type FIP3 but not FIP3 mutants lacking the binding site for Arf6 or Rab11. These results suggest that Arf6 regulates cortical neuronal migration in the intermediate zone through the FIP3-dependent endosomal trafficking.
在神经发育过程中，通过与细胞-细胞和细胞-细胞外基质相互作用相关的膜蛋白的极化运输，内体运输控制细胞的形状和运动。ADP 核糖基化因子 6（Arf6）是一种关键的小 GTP 酶，可调节质膜与内体之间的膜运输。本文证明，在小鼠大脑皮质中敲低内源性 Arf6 会导致中间区的神经元迁移受损，以及迁移神经元中 N-钙粘蛋白和突触素 12 的细胞质滞留。用分离功能的 Arf6 突变体进行的挽救实验鉴定了 Rab11 家族相互作用蛋白 3（FIP3）/Arfophilin-1，它是 Arf6 和 Rab11 的双重效应物，是迁移神经元中 Arf6 的下游效应物。FIP3 的敲低导致中间区的神经元迁移受损，以及迁移神经元中 N-钙粘蛋白的细胞质滞留，类似于 Arf6，其可以通过野生型 FIP3 的共表达来挽救，但不能通过缺乏 Arf6 或 Rab11 结合位点的 FIP3 突变体来挽救。这些结果表明，Arf6 通过 FIP3 依赖性内体运输来调节中间区的皮质神经元迁移。
