The Ig superfamily member SynCAM 1 functions in synaptic differentiation during early postnatal developmental stages and is sufficient to drive the formation of presynaptic specializations. Concurrently, SynCAM 1 promotes neurotransmission between neurons and exerts this activity specifically at glutamatergic synapses in the CNS. Only the neurexin/neuroligin adhesion system shares similar functions. Thus, these synaptic adhesion molecules not only bridge the synaptic cleft, but can also initiate subsequent steps of synapse formation. SynCAM 1 has been identified in additional physiological contexts, which could provide new directions in understanding this gene family. For example, SynCAM 1 may have neuroimmunological roles, as indicated by the fact that it engages in adhesion of neurites to mast cells49. SynCAM 1 also appears to have tumor suppressor activity28, which could be due to roles of this adhesion molecule in cell migration and differentiation. However, the best understood functions of SynCAM 1 to date are in synaptic differentiation.
Three key questions are the focus of current studies of SynCAM 1 in synaptogenesis. First, what are the intracellular interaction partners of SynCAM 1 that signal and organize the formation of synaptic membrane specializations? Several intracellular candidate proteins are known to interact with SynCAM 1, but the extent to which they function downstream remains to be investigated. Furthermore, it is likely that other adaptor and signaling molecules bind SynCAM 1, and their identification and characterization will prove critical for understanding SynCAM 1 function. Second, the extracellular interactions of SynCAM 1 need to be characterized in molecular detail. These studies will identify the extracellular partners of SynCAM 1 beyond its own homophilic binding. Candidate extracellular interacting proteins include the other SynCAM family members. Future questions will also include whether these Ig domain-mediated interactions are regulated by N- and O-glycosylation of the SynCAM 1 extracellular domain. Third, the physiological functions of SynCAM 1 in the brain will have to be further characterized using a combination of in vitro and in vivo approaches, notably mouse genetics.
These studies can lead to insights not only into the roles of SynCAM 1 in synapse induction, but also in other aspects of synaptic differentiation. The possibility that SynCAM 1 exerts functions subsequent to synapse induction is indicated by the fact that it remains expressed in adult animals after the peak of synaptogenesis has occurred. It is conceivable that SynCAM 1 promotes maturation and stability of synapses after they are formed. SynCAM 1 therefore could affect synaptic plasticity subsequent to triggering synapse formation. Since SynCAM 1 is the representative member of a small family of four highly conserved vertebrate genes expressed in the developing brain, their characterization may provide further insights into mechanisms of target recognition, synaptic specificity, and synapse differentiation mediated by these Ig superfamily members. Future studies are expected to throw light on the roles of SynCAM proteins at developing synapses and on the extent to which they affect synaptic function.
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