Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins

Abstract

The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.

Keywords: amyotrophic lateral sclerosis; axon pruning; dendritogenesis; neurodegeneration; neuromuscular junction; perineuronal net; plexins; retina; semaphorins; synaptic plasticity.

Figure 1

Semaphorins (SEMA/Sema) and Plexins (PLXN/Plex) diversity. Sema2s, SEMA3s and SEMAV are secreted proteins, while the others are membrane anchored (SEMA7A presents an additional glycosylphosphatidylinositol). Sema1s, Sema2s and Sema5c (not pictured here as its function is unknown) are present in invertebrates, while SEMAV is found in viral genome. All the remaining (SEMA3s to SEMA7A) are vertebrate Semaphorins. In the nervous system, Semaphorins are signaling directly through Plexins. Exception is made for SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3F and SEMA3G which are bound by Neuropilins (NRP) 1 or 2, and form a receptor complex with PLXNAs to initiate an intracellular pathway.

Figure 2

Synaptic plasticity in the neocortex and hippocampus. Schematics showing the different known Semaphorins-Plexins interactions during spinogenesis and plasticity. (A) Excitatory axons are colored in green, while inhibitory axons are colored in red, and respectively form excitatory and inhibitory synapses onto the post-synaptic neuron. (B) In the neocortex, excitatory synapse pruning is mediated by SEMA3B and SEMA3F, which signals through CHL1/NRP2/PLXNA4 and NrCAM/NRP2/PLXNA4, respectively. (C) In the hippocampus, inhibitory synapses are formed and stabilized by a complex interaction between SEMA4D and PLXNBs, present at both pre- and post-synaptic sites. Excitatory synaptogenesis is modulated by SEMA4A and PLXNB2 and may additionally rely on SEMA4B and SEMA4F. On the other hand, pruning is initiated by NRP2/PLXNA3 binding to SEMA3F. Finally, SEMA3G secreted by blood vessels interacts with NRP2/PLXNA4 to confer plasticity for new memory formation.