Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Am Klopferspitz, Martinsried, Germany.
EMBO J. 2011 Jun 14;30(14):2920-33. doi: 10.1038/emboj.2011.189.
Netrin-1 induces repulsive axon guidance by binding to the mammalian Unc5 receptor family (Unc5A-Unc5D). Mouse genetic analysis of selected members of the Unc5 family, however, revealed essential functions independent of Netrin-1, suggesting the presence of other ligands. Unc5B was recently shown to bind fibronectin and leucine-rich transmembrane protein-3 (FLRT3), although the relevance of this interaction for nervous system development remained unclear. Here, we show that the related Unc5D receptor binds specifically to another FLRT protein, FLRT2. During development, FLRT2/3 ectodomains (ECDs) are shed from neurons and act as repulsive guidance molecules for axons and somata of Unc5-positive neurons. In the developing mammalian neocortex, Unc5D is expressed by neurons in the subventricular zone (SVZ), which display delayed migration to the FLRT2-expressing cortical plate (CP). Deletion of either FLRT2 or Unc5D causes a subset of SVZ-derived neurons to prematurely migrate towards the CP, whereas overexpression of Unc5D has opposite effects. Hence, the shed FLRT2 and FLRT3 ECDs represent a novel family of chemorepellents for Unc5-positive neurons and FLRT2/Unc5D signalling modulates cortical neuron migration.
Netrin-1 通过与哺乳动物 Unc5 受体家族（Unc5A-Unc5D）结合诱导排斥性轴突导向。然而，对 Unc5 家族选定成员的小鼠遗传分析显示，它们具有独立于 Netrin-1 的重要功能，表明存在其他配体。最近已经证明 Unc5B 可以结合纤维连接蛋白和富含亮氨酸跨膜蛋白 3（FLRT3），尽管这种相互作用对神经系统发育的相关性尚不清楚。在这里，我们表明相关的 Unc5D 受体特异性结合另一种 FLRT 蛋白，FLRT2。在发育过程中，FLRT2/3 胞外结构域（ECD）从神经元中脱落，并作为 Unc5 阳性神经元的轴突和体的排斥性导向分子。在发育中的哺乳动物新皮层中，Unc5D 由室下区（SVZ）中的神经元表达，这些神经元显示出向表达 FLRT2 的皮质板（CP）的迁移延迟。FLRT2 或 Unc5D 的缺失会导致一部分 SVZ 来源的神经元过早地向 CP 迁移，而过表达 Unc5D 则会产生相反的效果。因此，脱落的 FLRT2 和 FLRT3 ECD 代表了一类新型的 Unc5 阳性神经元趋化因子，FLRT2/Unc5D 信号调节皮质神经元迁移。
