Molecular continuity between axon guidance and synaptic function

The precise assembly of neural circuits is a marvel of cellular engineering, requiring the seamless coordination of long-range axon navigation and short-range synapse formation. Traditionally, these 2 processes were thought to be governed by distinct sets of molecular cues. However, emerging evidence challenges this dichotomy, revealing that proteins canonically associated with mature synaptic transmission are "repurposed" early in development to instruct selective neuronal pairing, including axon guidance and target recognition. In this mini-review, we discuss the molecular versatility of key synaptic proteins, including latrophilins, N-methyl-D-aspartate receptors, cerebellins, neurexins, and other complementary adhesion systems. We highlight how these molecules utilize non-canonical mechanisms, such as ion flux-independent signaling and trans-neuronal adhesion, to couple initial wiring decisions with later synaptic specialization. This functional duality suggests a "molecular continuum" in brain development, offering broader insights into how cells maximize their proteomic toolkit to build complex biological systems.