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FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons

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Yamagishi, S., Hampel, F., Hata, K., del Toro, D., Schwark, M., Kvachnina, E., et al. (2011). FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO JOURNAL, 30(14), 2920-2933. 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 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