Netrins

Netrins are a family of secreted guidance cues that orchestrate axon pathfinding and cell migration during development. They are secreted proteins related to laminin and were first identified in Caenorhabditis elegans as UNC-6, a molecule that directs commissural axons. In vertebrates, the netrin family includes several members, with netrin-1 (NTN1) being the best studied.

Netrins are secreted glycoproteins that can form gradients, guiding growing axons toward or away from a source. They exert their effects through a set of receptors and can influence multiple cell types. The best characterized receptors are DCC (Deleted in Colorectal Cancer) and the UNC5 family (UNC5A–D). Binding to DCC generally mediates attraction, while interaction with UNC5 receptors can mediate repulsion or, in combination with DCC, modulate response. Neogenin (NEO1) and other receptor partners can modulate signaling outcomes as well.

Functions and roles: Netrin signaling guides axon pathfinding in the central and peripheral nervous systems and influences neuronal migration during development. Beyond the nervous system, netrins participate in vascular development, angiogenesis, and tissue morphogenesis, affecting endothelial cell behavior and organ formation. Their signaling pathways interact with cytoskeletal regulators and influence cell survival and organization.

Clinical relevance and research notes: DCC is a known tumor suppressor, and netrin-1 can act as a survival factor by inhibiting apoptosis mediated by DCC, a mechanism explored in cancer therapy. Disruptions in netrin signaling have been linked to neurodevelopmental disorders and vascular abnormalities in model systems. Netrins are conserved across species, and ongoing research continues to clarify receptor networks and downstream effects.