semaphorines

Semaphorins are a family of secreted and membrane-associated proteins that regulate cell guidance and organization in development and in adult tissues. They were first identified as neural guidance cues and are now known to influence processes beyond the nervous system, including vascular formation and immune responses. The term semaphorin denotes a broad, evolutionarily conserved set of signaling molecules that coordinate cellular movement and patterning.

Molecular structure and classification: Most semaphorins share an extracellular sema domain, a large, proteoglycan-like region that mediates receptor interaction. Many members also contain additional domains such as PSI and Ig-like modules, and most are anchored to the cell surface by a transmembrane region. In vertebrates, semaphorins are classified into several classes (commonly class 3 being secreted and classes 1, 2, 4–7 being membrane-associated). Receptors of semaphorins are primarily Plexins, which transmit signals inside the cell, and Neuropilins (NRP1/NRP2) that act as co-receptors for certain class 3 semaphorins.

Signaling and function: Binding of semaphorins to Plexins triggers intracellular signaling cascades that regulate the actin and microtubule cytoskeleton. This control can cause growth cone collapse or steering of axons, contributing to proper neural wiring. Depending on the specific ligand-receptor combination, semaphorins can function as repellents or attractants. In addition to neural guidance, semaphorins influence angiogenesis, immune cell behavior, and tissue morphogenesis.

Distribution and evolution: Semaphorins are widely expressed across tissues and organisms, with diversified family members enabling tissue- and context-specific roles. The family has expanded through gene duplication, allowing specialization in different lineages.

Clinical and research relevance: Dysregulation of semaphorin signaling is associated with neurodevelopmental disorders, neurodegenerative diseases, cancer progression, and immune dysfunction. As integrators of cell movement and organization, semaphorins remain active targets for research and potential therapeutic intervention.