Semaphorins are phylogenetically conserved proteins expressed in most organ systems, including the nervous system. Following their description as axon guidance cues, semaphorins have been implicated in multiple aspects of nervous system development. Semaphorins are key regulators of neural circuit assembly, neuronal morphogenesis, assembly of excitatory and inhibitory synapses, and synaptic refinement. Semaphorins contribute to the balance between excitatory and inhibitory synaptic transmission, and electrical activity can modulate semaphorin signaling in neurons. This interplay between guidance cue signaling and electrical activity has the potential to sculpt the wiring of neural circuits and to modulate their function.
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