SynCAMs

Introduction

In mammals, synaptic cell adhesion molecules (SynCAMs) are a family of four proteins (SynCAM1-4) belonging to the immunoglobulin (Ig) superfamily of cell adhesion molecules. SynCAMs are encoded by the cell adhesion molecule CADM1-4 genes. Structurally, SynCAMs are single transmembrane-spanning proteins that could be divided into an extracellular domain containing three extracellular Ig binding domains, a small intracellular region containing two short protein interaction sequences, and a short cytoplasmic tail with protein interaction motifs predicted to bind cytoskeletal regulators and scaffolding molecules.

Fig.1 Model of the SynCAM 1 constructs. (Fogel, 2011)

Action Mechanism

SynCAM 1 and SynCAM 2 are expressed in neurons in the developing brain and localize to inhibitory and excitatory synapses. SynCAMs team up for synaptogenesis: SynCAM 1 and SynCAM 2 assemble into a trans-synaptic adhesive complex. By recruiting scaffold molecules, they organize functional synapses and promote transmission. The interaction between SynCAM 1 and SynCAM 2 is affected by glycosylation, suggesting regulation of this adhesion complex by posttranslational modification (PTM). As Figure 2 shown, Cis-binding is mediated by the Ig-domains 2 and 3. Trans interaction requires Ig-domain 1. Predicted N-glycosylation sites were found in Ig1 and Ig3.

Fig.2 Glycosylation regulates SynCAM cis- and trans-interactions. (Frei, 2014)

Function and Neurodevelopmental Disorders

SynCAMs have multiple functions at the synapse. They trigger synaptogenesis, contribute to synaptic organization, specification, and maturation, but are also important for the maintenance and plasticity of synapses. In line with a function in synaptogenesis, synaptic organization, and plasticity, mutations in SynCAMs have been identified as causes or risk factors for neurodevelopmental disorders, especially intellectual disability and autism spectrum disorder (ASD). Up to now, two missense mutations in SynCAM1, H246N, and Y251S, have been identified in patients with ASD. Notably, the two missense mutations are in the third Ig-domain of SynCAM1, a region that is important for homo and heterophilic adhesion.

Latest Research Progress

A recent study reported three main observations that enhance understanding of SynCAM synaptogenic functions:

• Only triple Knockdown of SynCAM1-3 reduced synapse number, implying functional compensation during synapse formation.
• Triple Knockdown increased synapse and miniature excitatory postsynaptic currents (mEPSC) size, suggesting intact SynCAM1-3 signaling functions redundantly to limit the physical size of trans-synaptic complexes.
• Use of MEDLR provides strong evidence that postsynaptic, SynCAM1-3 regulates synapse density and size.

Related Products or Services

To learn more about disease mechanisms, animal models are required. It is impossible to develop appropriate animal models to reproduce the classical autism symptoms. Single and multi-gene knockdown lentiviral constructs are indispensable research tools. For customized SynCAMs services or products, please feel free to contact us for cooperation.

References

1. Fogel, A. I.; et al. Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation. The EMBO journal. 2011, 30(23): 4728-4738.
2. Frei, J. A.; Stoeckli, E. T. Syn CAM s extend their functions beyond the synapse. European Journal of Neuroscience. 2014, 39(11): 1752-1760.