Analysis of FLRT family proteins as novel axon guidance molecules

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The mammalian Unc5 family of repulsive Netrin receptors comprises four orthologues (Unc5A-D) whose functions are not well understood. In the developing neocortex, a subpopulation of neurons in the subventricular zone (SVZ) characterized by the expression of Unc5D, displays delayed migration to the cortical plate (CP). However, the underlying mechanism of this behavior is unknown. Unc5D was shown to bind Fibronectin and leucine-rich transmembrane protein-3 (FLRT3), the relevance of which is unclear. We show that FLRT2, which is expressed in the CP, is a new ligand for Unc5D. In FLRT2 or Unc5D mutants, a subpopulation of SVZ neurons shows premature migration towards the CP, whereas Unc5D overexpression has opposite effects. These findings suggest that FLRT2 represents a repulsive guidance cue that causes Unc5D+ neurons to reside in the SVZ for a prolonged period before initiating migration.