Cracking the cadherin codes that wire the nervous system

Synaptic partner recognition and precise connectivity are essential components of neural circuit formation and function. Cell adhesion molecules with selective binding properties provide instructive cues for synapse specificity. Yet, we know little about how they guide the stereotyped organization of neural circuits. Advances in transcriptomics, genetic manipulations, neural tracing and imaging in intact nervous systems enable new avenues to identify mechanisms by which adhesion molecules regulate synapse specificity. Here we discuss the Cadherin superfamily, which forms one of the most functionally versatile families of cell adhesion molecules. Focusing on the classical cadherins and clustered protocadherins, we discuss recent findings that demonstrate roles in regulating synaptic partnerships and signaling properties, and optimizing neurite wiring. We highlight studies that demonstrate instructive roles through genetic manipulations with assays of synaptic connectivity. Understanding how neurons leverage a Cadherin code for specifying neural connectivity provides insights into the broader principles of circuit assembly and function.