- Semaphorin 3A (Sema3A) is a secreted glycoprotein that belongs to the class 3 semaphorins, a family of signaling molecules originally identified for their role in axonal guidance during neural development.
- Encoded by the SEMA3A gene, Sema3A functions as a chemorepulsive cue, directing neuronal growth cones away from inappropriate targets and helping establish precise neuronal connections in the developing nervous system.
- It exerts its biological effects through binding to neuropilin-1 (NRP1) as its primary receptor and plexin-A family proteins as co-receptors, forming receptor complexes that activate intracellular signaling pathways. These pathways regulate cytoskeletal dynamics, leading to growth cone collapse, axon repulsion, and neuronal patterning.
- Beyond its classical role in the nervous system, Sema3A has emerged as a multifunctional molecule with critical functions in angiogenesis, immune regulation, bone homeostasis, and cancer. In the vascular system, Sema3A competes with vascular endothelial growth factor (VEGF) for binding to neuropilin-1, thereby inhibiting VEGF-induced angiogenesis. This antagonistic relationship makes Sema3A a negative regulator of vascular growth and permeability, influencing both physiological and pathological vascular remodeling. In the immune system, Sema3A modulates T-cell and dendritic cell migration, serving as an immunoregulatory factor that shapes immune responses and contributes to immune tolerance.
- In bone biology, Sema3A plays an important role in maintaining the balance between bone formation and resorption. It promotes osteoblast differentiation while inhibiting osteoclast activity, thereby exerting a net bone-protective effect. Animal studies have demonstrated that Sema3A deficiency leads to reduced bone mass and impaired skeletal homeostasis, while therapeutic administration of Sema3A can enhance bone regeneration. These findings highlight its potential as a therapeutic target for osteoporosis and other bone-related disorders.
- In the context of cancer, Sema3A exhibits complex, context-dependent roles. On one hand, its anti-angiogenic and immune-modulating properties suggest tumor-suppressive functions, as Sema3A can limit tumor vascularization and immune evasion. On the other hand, some tumors exploit Sema3A signaling for survival and dissemination, with studies indicating that its expression may promote metastasis in certain cancers by influencing cell migration and tumor–stroma interactions. The dual role of Sema3A in cancer reflects the intricacy of its signaling networks, which can either suppress or support tumor progression depending on the cellular and microenvironmental context.
- Clinically, Sema3A has attracted attention as both a biomarker and a therapeutic target. Altered expression levels of Sema3A have been reported in neurological disorders, autoimmune diseases, and malignancies. In multiple sclerosis, for example, Sema3A is upregulated and may contribute to axonal damage and impaired remyelination, making it a potential therapeutic target for neuroprotection. Conversely, in cardiovascular and ischemic diseases, strategies to enhance Sema3A activity have been proposed to stabilize blood vessels and reduce pathological angiogenesis.
