Laboratory of Membrane Trafficking, Center for Human Genetics, KU Leuven, Leuven, Belgium.
EMBO J. 2012 Aug 1;31(15):3252-69. doi: 10.1038/emboj.2012.182. Epub 2012 Jul 10.
Dendritic filopodia are dynamic structures thought to be the precursors of spines during synapse development. Morphological maturation to spines is associated with the stabilization and strengthening of synapses, and can be altered in various neurological disorders. Telencephalin (TLN/intercellular adhesion molecule-5 (ICAM5)) localizes to dendritic filopodia, where it facilitates their formation/maintenance, thereby slowing spine morphogenesis. As spines are largely devoid of TLN, its exclusion from the filopodia surface appears to be required in this maturation process. Using HeLa cells and primary hippocampal neurons, we demonstrate that surface removal of TLN involves internalization events mediated by the small GTPase ADP-ribosylation factor 6 (ARF6), and its activator EFA6A. This endocytosis of TLN affects filopodia-to-spine transition, and requires Rac1-mediated dephosphorylation/release of actin-binding ERM proteins from TLN. At the somato-dendritic surface, TLN and EFA6A are confined to distinct, flotillin-positive membrane subdomains. The co-distribution of TLN with this lipid raft marker also persists during its endosomal targeting to CD63-positive late endosomes. This suggests a specific microenvironment facilitating ARF6-mediated mobilization of TLN that contributes to promotion of dendritic spine development.
树突丝状伪足是一种动态结构，被认为是突触发育过程中棘突的前体。形态成熟为棘突与突触的稳定和强化有关，并可在各种神经紊乱中发生改变。端脑蛋白 (TLN/细胞间黏附分子-5 (ICAM5)) 定位于树突丝状伪足，在那里它促进其形成/维持，从而减缓棘突形态发生。由于棘突基本上不含 TLN，因此其从丝状伪足表面的排除似乎是这个成熟过程所必需的。我们使用 HeLa 细胞和原代海马神经元证明，TLN 的表面去除涉及由小分子 GTPase 激活蛋白 6 (ARF6) 和其激活因子 EFA6A 介导的内化事件。这种 TLN 的内吞作用影响丝状伪足向棘突的转变，并且需要 Rac1 介导的从 TLN 上释放肌动蛋白结合 ERM 蛋白的去磷酸化/释放。在体树突状表面，TLN 和 EFA6A 局限于不同的、 flotillin 阳性的膜亚域。在其靶向到 CD63 阳性晚期内体的过程中，TLN 与这个脂筏标记物的共分布也持续存在。这表明一个特定的微环境有利于 ARF6 介导的 TLN 动员，有助于促进树突棘突的发育。
