Institut für Anatomie und Zellbiologie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
J Neural Transm (Vienna). 2009 Nov;116(11):1451-5. doi: 10.1007/s00702-009-0228-7. Epub 2009 Apr 25.
Reelin is a large extracellular matrix molecule, synthesized by early generated Cajal-Retzius cells in the marginal zone of the cortex. It plays an important role in the migration of cortical neurons and the development of cortical lamination. We recently discovered that Reelin is required not only for the formation of cortical layers during development but also for their maintenance in adulthood. Thus, decreased Reelin expression in a mouse model of epilepsy and in epileptic patients was accompanied by a loss of granule cell lamination, called granule cell dispersion, in the dentate gyrus of the hippocampal formation. Moreover, antibody blockade of Reelin in normal, adult mice resulted in granule cell dispersion. Collectively these findings point to a role for Reelin in the formation and maintenance of a laminated cortical structure. How does Reelin act on the cytoskeleton in the migration process of cortical neurons? It has been shown that Reelin signalling involves the lipoprotein receptors apolipoprotein E receptor 2 and very low density lipoprotein receptor, the adapter protein Disabled1, and phosphatidylinositol-3-kinase, but it has remained unclear how activation of the Reelin signalling cascade controls cytoskeletal reorganization. Here, we provide evidence that Reelin signalling leads to serine3 phosphorylation of cofilin, an actin-depolymerizing protein that promotes the disassembly of F-actin. Phosphorylation at serine3 renders cofilin unable to depolymerize F-actin, thereby stabilizing the cytoskeleton. Phosphorylation of cofilin in the leading processes of migrating neurons anchors them to the marginal zone containing Reelin. Our results indicate that Reelin-induced stabilization of the neuronal cytoskeleton is an important component of Reelin's function in the development and maintenance of cortical architecture.
Reelin 是一种大型细胞外基质分子，由皮质边缘区的早期 Cajal-Retzius 细胞合成。它在皮质神经元的迁移和皮质层的发育中起着重要作用。我们最近发现，Reelin 不仅在发育过程中形成皮质层中起作用，而且在成年期维持皮质层中起作用。因此，在癫痫的小鼠模型和癫痫患者中 Reelin 的表达减少伴随着海马结构齿状回颗粒细胞层的丧失，称为颗粒细胞弥散。此外，在正常成年小鼠中，Reelin 的抗体阻断导致颗粒细胞弥散。这些发现共同表明 Reelin 在分层皮质结构的形成和维持中起作用。Reelin 在皮质神经元迁移过程中如何作用于细胞骨架？已经表明 Reelin 信号涉及脂蛋白受体载脂蛋白 E 受体 2 和极低密度脂蛋白受体、衔接蛋白 Disabled1 和磷脂酰肌醇-3-激酶，但 Reelin 信号级联的激活如何控制细胞骨架重组仍不清楚。在这里，我们提供的证据表明，Reelin 信号导致丝氨酸 3 磷酸化，丝氨酸 3 磷酸化的 cofilin 是一种肌动蛋白解聚蛋白，可促进 F-actin 的解聚。磷酸化的 cofilin 无法解聚 F-actin，从而稳定细胞骨架。迁移神经元的先导过程中的 cofilin 磷酸化将它们锚定在含有 Reelin 的边缘区。我们的结果表明，Reelin 诱导的神经元细胞骨架稳定是 Reelin 在皮质结构发育和维持中的功能的重要组成部分。
