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 Netrin Signaling

Netrins, slits, semaphorins and ephrins are highly conserved families of guidance molecules that facilitate the development of neuronal circuits. These molecules provide attractive and repulsive guidance signals to direct neural and axonic pathfinding.

Netrins (UNC-6) are a family of secreted proteins that function as tropic guidance cues directing cell and axon migration. Netrin-1 is a guidance factor that can attract or repel axon out-growth. This dual activity is dependent upon the presence of distinct receptors, cell type and context. Netrin-1 produces attractive effects via receptors of the deleted in colorectal cancer (DCC) family which includes the vertebrate-associated receptors, DCC and neogenin, the C. elegans receptor, UNC-40 and the Frazzled protein of Drosophila. Netrin-1 mediates repulsive effects through UNC-5 receptors, represented in humans by UNC5H1, UNC5H2, and UNC5H3/RCM. DCC can also mediate repellant responses. The DCC response to netrin-1 binding can be switched between attractant and repellant by signaling factors and context. Protein kinase A (PKA) is a switching factor.

DCC is involved in cell survival. DCC is anti-apoptotic when occupied by agonists, such as Netrin-1. However, unoccupied DCC can promote intrinsic (mitochondria-dependent)-independent caspase 9-dependent apoptosis. Netrin-1 binding to DCC promotes axon cone growth through the activation of the Rho GTPases, Cdc42 and Rac1, and their downstream effectors, PAK1 and N-WASP, and through Drosophila enabled/vasodilator-stimulated phosphoprotein (Ena/VASP). The Rho GTPases which are linked to the receptor via Nck-1 facilitate actin reorganization and cone progression through filopodia, membrane ruffling and lammellipodia. Ena is associated with filament anchoring dynamics. Attractant activity of agonist occupied DCC is also dependent upon protein kinase A (PKA). PKA promotes the movement of DCC to the plasma membrane from a cytoplasmic pool.