Cell Adhesion Molecules - synapse formation

Post date: May 4, 2011 2:24:41 PM

Cell adhesion molecules (CAMs) perform many functions at the synapse. Although initially, CAMs were believed to play only a structural role as molecular anchors for nascent synapses, experimental evidence has subsequently shown that they are also involved in target recognition (Yamagata et al., 2002, Shen and Bargmann, 2003, Shen et al., 2004, Margeta et al., 2008, Margeta and Shen, 2010), synaptic size regulation and even control of synaptic strength (Scheiffele, 2003, Yamagata et al., 2003). These roles suggest CAMs are involved in some form of signal transduction. In fact, some evidence suggests that membrane-bound CAMs are able to trigger synapse formation (Scheiffele et al., 2000, Biederer et al., 2002, Sytnyk et al., 2002, Fu et al., 2003) by acting as ligand, receptor or both. Some well-studied, non-synaptic examples of CAMs having signaling roles include cadherins and immunoglobulin (Ig) family members. Cadherins signal through catenin (Figure 3). Some Ig family members such as N-CAM associate with Src family cytoplasmic tyrosine kinases, which relay signals by phosphorylating intracellular protein tyrosine residues. Other Ig family members such as the PTPδ proteins (Gonzalez-Brito and Bixby, 2006) are transmembrane tyrosine phosphatases that help guide growing axons to their target cells.

After initial contact, synaptogenesis requires recruitment of presynaptic proteins including vesicle fusion machinery and the appropriate neurotransmitter specific proteins on the presynaptic side, and postsynaptic proteins including neurotransmitter receptors and associated signaling molecules to the postsynaptic side. These trans-synaptic signals presumably involve great specificity.

Due to the presence of multiple isoforms of cadherins in axons and dendrites, they may be the CAMs that promote selective adhesion between neurons and their proper partners. All three types of cadherins: classical cadherins, cadherin-related proteins, and protocadherins are expressed in the mammalian central nervous system (CNS). The expression of cadherins varies with neuronal cell type, sub-cellular compartment and developmental stage, as does the expression of their intracellular binding partners, the catenins. This suggests that cadherins may play a role in developmental synapse specificity.

At individual synapses, classical cadherins are detected pre- and postsynaptically (Benson and Huntley, 2010, Jontes et al., 2004, Togashi et al., 2002). N-cadherin and β-catenin are distributed diffusely along the length of dendritic filopodia. Upon contact with an axon, the cadherin complex accumulates at points of contact (Jontes et al., 2004, Togashi et al., 2002). Studies of a dominant negative N-cadherin (lacking the ectodomain), demonstrate that loss of cadherin function results in the loss of spines (Jontes et al., 2004). Initial synaptic assembly is delayed, but not blocked, in neurons transfected with dominant-negative cadherins (Bozdagi et al., 2004). This suggests that cadherins are important for target recognition, but are not essential for synaptogenesis per se.

Protocadherins have also been implicated in target selection. About 70 protocadherins have been identified in mice and humans, many of which are expressed in the nervous system. They are expressed in overlapping patterns for the most part, but some differences in strength of expression have been demonstrated (Frank et al., 2005, Frank and Kemler, 2002). Unfortunately, deletion of all of the variable exons in the protocadherin-γ cluster leads to neonatal lethality (Wang et al., 2002), which makes it difficult to assess what role they might play in target specificity. However, when combined with a mutation that prevents apoptosis, protocadherin-γ mutant neurons made significantly fewer synapses than wild-type neurons (Weiner et al., 2005).

In mammals, proteins called sidekicks are Ig superfamily cadherin-like proteins. Sidekick-1 is concentrated at presynaptic sites, and sidekick-2 is localized to postsynaptic areas. They are expressed in a generally non-overlapping set of retinal neurons (Yamagata et al., 2002). Heterologous cells that express sidekick-1 or sidekick-2 make cellular aggregates. This suggests that their interactions can be homophilic. Deletion of the first two Ig domains of both sidekick-1 and sidekick-2 abolishes this interaction (Hayashi et al., 2005), suggesting that these domains are required for interaction.