semaphorins

Semaphorins are a conserved family of secreted and membrane-associated proteins that guide cell and axon navigation during development and in adult tissues. First identified as axon guidance cues in the nervous system, semaphorins influence neuronal growth, dendrite patterning, and synapse formation, and also regulate vascular development, immune cell interactions, and tissue remodeling.

Semaphorins share a conserved extracellular sema domain of about 500 amino acids and are categorized into several classes. In vertebrates, Sema3 family members are secreted, whereas Sema4–Sema7 are primarily membrane-associated. Receptors for semaphorins belong mainly to the plexin family, with neuropilins acting as co-receptors for class 3 semaphorins.

Signaling downstream of plexins modulates cytoskeletal dynamics via Rho-family GTPases and effectors such as CRMPs and Mical, producing growth cone collapse, repulsion, or, in some contexts, adhesion and attraction. The outcome depends on the semaphorin class, receptor combination, and cellular environment.

Semaphorin signaling is implicated in neural circuit assembly, guidance of migrating neurons, angiogenesis, immune responses, and cancer progression. Misregulation of semaphorin pathways is associated with neurodevelopmental disorders, retinal diseases, autoimmune conditions, and metastasis.

Semaphorins are present across metazoans, and gene diversification has produced a wide repertoire of receptors and signaling partners. Research continues to explore semaphorin pathways as targets in neuroregeneration, oncology, and immunology.