UNC5

UNC5 refers to a family of netrin receptors that mediate axon guidance, neuronal migration, and tissue morphogenesis in development. In vertebrates the family comprises four paralogous genes: UNC5A, UNC5B, UNC5C, and UNC5D. The UNC5 receptors are evolutionarily conserved, with orthologs present in invertebrates such as the C. elegans unc-5 gene.

Molecularly, UNC5 proteins are single-pass transmembrane receptors. Their extracellular region contains immunoglobulin-like domains and thrombospondin type 1 repeats that bind netrin ligands, most notably netrin-1. The intracellular region includes a death domain, which is central to their signaling as dependence receptors.

A defining feature of UNC5 receptors is their role as dependence receptors. In the absence of netrin-1, UNC5 receptors can initiate apoptotic signaling through the intracellular death domain, promoting cell death. Binding netrin-1 inhibits this pro-apoptotic signaling and supports survival. In terms of guidance cues, UNC5 receptors often function in the context of netrin receptor signaling, frequently cooperating with DCC (the deleted in colorectal cancer receptor) to interpret netrin-1 cues and influence directional growth of axons and migrating neurons. The outcome—attraction, repulsion, or changes in migration—depends on receptor composition and cellular context.

Expression of UNC5A–D is broad but varies by tissue and developmental stage, with prominent roles in the nervous system during development and in various organs thereafter. Clinically, UNC5 family members have been studied as tumor suppressors, with altered expression observed in several cancers, reflecting their role in regulating cell survival in response to guidance cues.