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Free keywords:
C-6147-2008CELL-ADHESION; SUBVENTRICULAR ZONE; NEURITE OUTGROWTH; RECEPTOR GENE;
AXON GUIDANCE; MIGRATION; MOLECULE; PROTEIN; IDENTIFICATION;
SPECIFICATIONcell migration; cortex development; FLRT; repulsive guidance; Unc5;
Abstract:
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
