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

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Netrin-1 binding to Unc5 receptors mediates repulsive axon guidance.
• Unc5 family members have Netrin-1-independent functions, suggesting alternative ligands.
• Unc5B interacts with fibronectin and leucine-rich transmembrane protein-3 (FLRT3), but its role in nervous system development is unclear.

Purpose of the Study:

• To investigate the interaction between Unc5D and FLRT proteins.
• To determine the role of FLRT2/Unc5D signaling in nervous system development, specifically cortical neuron migration.

Main Methods:

• Investigated Unc5D binding to FLRT proteins.
• Analyzed the function of shed FLRT2/3 ectodomains as guidance molecules.
• Utilized mouse genetic models with deletions or overexpression of FLRT2 and Unc5D.
• Examined neuron migration in the developing mammalian neocortex.

Main Results:

• Unc5D specifically binds to FLRT2.
• Shed FLRT2 and FLRT3 ectodomains function as repulsive guidance cues for Unc5-positive neurons.
• FLRT2/Unc5D signaling modulates the migration of subventricular zone (SVZ)-derived neurons to the cortical plate (CP).
• Deletion of FLRT2 or Unc5D leads to premature migration of SVZ neurons, while Unc5D overexpression delays migration.

Conclusions:

• Shed FLRT2 and FLRT3 ectodomains represent a novel class of chemorepellents for Unc5-positive neurons.
• FLRT2/Unc5D signaling is a key regulator of cortical neuron migration during mammalian brain development.