FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons
2011
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.
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