Synaptic organizing complexes

Abstract

A number of synaptogenic factors induce presynaptic or postsynaptic differentiation when presented to axons or dendrites. Many such factors participate in bidirectional trans-synaptic adhesion complexes. Axonal neurexins interacting in an isoform-specific code with multiple dendritic partners (neuroligins, LRRTMs, or Cbln-GluRδ), and axonal protein tyrosine phosphatase receptors interacting with dendritic NGL-3, nucleate local networks of high-affinity protein-protein interactions leading to aligned presynaptic and postsynaptic differentiation. Additional secreted target-derived factors such as fibroblast growth factors and glial-derived factors such as thrombospondin bind specific axonal or dendritic receptors stimulating signal transduction mechanisms to promote selective aspects of synapse development. Together with classical adhesion molecules and controlled by transcriptional cascades, these synaptogenic adhesion complexes and secreted factors organize the molecular composition and thus functional properties of central synapses.

Figure 1

An inventory of synaptogenic molecules, defined here as proteins that induce presynaptic (←) or postsynaptic (→) differentiation when presented to axons or dendrites, respectively. Many of the adhesion complexes have bidirectional synaptogenic activity (↔). The main receptors are also shown for the secreted synaptogenic factors. PDZ domain binding sites and common protein domains are indicated.

Figure 2

Different initial mechanisms by which synaptogenic molecules promote synaptic differentiation. (a) Many synaptogenic adhesion complexes function primarily by nucleating a dynamic network of local high affinity protein-protein interactions in which each component interacts with multiple other components. (b) Many of the secreted factors directly activate signal transduction cascades involving kinases and GTPases, and perhaps regulate transcription. However, there are no strict boundaries, synaptogenic adhesion proteins can be kinases (e.g. Ephs) and secreted factors can act by local aggregation (e.g. NP1/2). These initial mechanisms are likely to converge on common downstream pathways mediating aspects of synaptic differentiation.