FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons
FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons
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DOI：
10.1038/emboj.2011.189
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发表时间：
2011-07-20
期刊：
影响因子：
11.4
通讯作者：
Egea, Joaquim
中科院分区：
文献类型：
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作者：
Yamagishi, Satoru;Hampel, Falko;Egea, Joaquim
Netrin-1通过结合哺乳动物Unc 5受体家族（Unc 5A-Unc 5D）诱导排斥性轴突导向。然而，对Unc 5家族的选定成员进行的小鼠遗传分析揭示了独立于Netrin-1的基本功能，表明存在其他配体。Unc 5 B最近被证明可以结合纤连蛋白和富含亮氨酸的跨膜蛋白3（FLRT 3），尽管这种相互作用与神经系统发育的相关性尚不清楚。在这里，我们表明，相关的Unc 5D受体特异性结合到另一个FLRT蛋白，FLRT 2。在发育过程中，FLRT 2/3胞外域（ECD）从神经元脱落，并作为Unc 5阳性神经元轴突和胞体的排斥性引导分子。在发育中的哺乳动物新皮质中，Unc 5D由脑室下区（SVZ）中的神经元表达，其显示延迟迁移到FLRT 2表达皮质板（CP）。FLRT 2或Unc 5D的缺失导致SVZ衍生的神经元的子集过早地向CP迁移，而Unc 5D的过表达具有相反的效果。因此，脱落FLRT 2和FLRT 3 ECD代表Unc 5阳性神经元的化学排斥物的新家族，并且FLRT 2/Unc 5D信号传导调节皮质神经元迁移。The EMBO Journal（2011）30，2920-2933. doi：10.1038/daj.2011.189; 2011年6月14日在线发布
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 sub-ventricular 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. The EMBO Journal ( 2011) 30, 2920-2933. doi:10.1038/emboj.2011.189; Published online 14 June 2011