Netrin

Netrins are a family of secreted, laminin-related guidance cues that regulate axon guidance and cell migration during animal development. They were first identified in the nematode Caenorhabditis elegans as UNC-6 and later found to be conserved in vertebrates, where several netrin family members have been described, including netrin-1, netrin-3, and netrin-4.

In the nervous system, netrins can act as attractive or repulsive signals depending on receptor composition. The DCC (Deleted in Colorectal Cancer) receptor generally mediates attraction to netrin, while UNC5 family receptors promote repulsion. Coexpression of DCC and UNC5 can modify the response, and other receptors such as neogenin can participate in netrin signaling. Binding of netrin to these receptors triggers intracellular signaling pathways that reorganize the cytoskeleton to steer growing axons.

Netrin-1 is strongly expressed at the embryonic midline in the spinal cord and brain, providing a diffusible cue that guides commissural neurons across the midline. Netrins also influence neuronal migration, axon targeting, and the formation of neural circuits in various regions. In addition to neural roles, netrins contribute to angiogenesis and the patterning of other tissues during development.

In adult tissues, netrin signaling continues to affect cell adhesion, migration, and synaptic organization in some contexts. Dysregulation of netrin signaling has been associated with diseases, notably cancer, where DCC is a historical tumor suppressor gene and netrin-1 overexpression or misregulation can promote tumor cell survival by signaling through its receptors. Because of this, therapies that disrupt netrin-1–receptor interactions are being explored in oncology.