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Synaptic cell adhesion molecules (SynCAMs) are crucial for synapse formation and plasticity. However, we have previously demonstrated that SynCAMs are also required during earlier stages of neural circuit formation because SynCAM1 and SynCAM2 (also known as CADM1 and CADM2, respectively) are important for the guidance of post-crossing commissural axons. In contrast to the exclusively homophilic cis-interactions reported by previous studies, our previous in vivo results suggested the existence of heterophilic cis-interactions between SynCAM1 and SynCAM2. Indeed, as we show here, the presence of homophilic and heterophilic cis-interactions modulates the interaction of SynCAMs with trans-binding partners, as observed previously for other immunoglobulin superfamily cell adhesion molecules. These in vitro findings are in agreement with results from in vivo studies, which demonstrate a role for SynCAMs in the formation of sensory neural circuits in the chicken embryo. In the absence of SynCAMs, selective axon-axon interactions are perturbed resulting in aberrant pathfinding of sensory axons.