Functions of axon guidance molecules in synapse formation

Abstract

Axon guidance and synapse formation are important developmental events for establishing a functional neuronal circuitry. These two related cellular processes occur in a coordinated fashion but previous studies from multiple model organisms seemed to suggest that axon guidance and synapse formation are mediated by distinct molecular cues. Thus, axon guidance molecules are responsible for guiding the navigating axon toward its target area, while other adhesion or ligand-receptor molecules specify the synapse formation within the target area. However, accumulative evidence has shown that axon guidance molecules can regulate the localization and formation of pre-synaptic and post-synaptic components during synapse formation. These results demonstrate a role for axon guidance molecules in synapse formation and provide insight into how axon guidance and synapse formation are coordinated at the molecular level.

Figure 1. Schematic illustrations of the processes of axon guidance and synapse formation

(a) The axon trajectory can be divided into multiple segments between guideposts. The guidance process between each guidepost is mediated by four types of forces, long-range chemoattraction or chemorepulsion, and short-range contact-mediated attraction or contact-mediated repulsion. (b) Synapse formation is a process of forming specialized pre- and post-synaptic structures for neurotransmission. It includes cell-cell contact, assembly of the presynaptic active zone for neurotransmitter release, and clustering of postsynaptic receptors in the post-synaptic density (PSD). Guideposts within the target area can provide spatial cues to instruct synapse formation.

Figure 2. Mechanisms of axon guidance molecules in synapse formation

Four general molecular mechanisms are utilized by axon guidance molecules to regulate synapse formation. Molecular attractions have pro-synaptogenic effects, while molecular repulsions result in anti-synaptogenic effects. Chemoattractants (green radial gradient) regulate subcellular cytoskeletal dynamics to facilitate synapse formation and recruit synaptic components to build up neurotransmission machinery in pre- and post-synaptic cells. Contact-mediated attractants (green bar) use similar mechanisms to stabilize the initial synaptic contact and promote the maturation of pre- and post-synaptic structures. In contrast, chemorepellents (red radial gradient) and contact-mediated repellents (red bar) have opposite effects to inhibit synapse formation.