Ten3-Lphn2-mediated target selection across the extended hippocampal network demonstrates a repeated strategy for circuit assembly

How do thousands of cell-surface proteins specify billions of neuronal connections in developing brains? We previously found that inverse expression of a ligand-receptor pair, teneurin-3 (Ten3) and latrophilin-2 (Lphn2) in CA1 and subiculum, instructs CA1[->]subiculum target selection through Ten3-Ten3 homophilic attraction and Ten3-Lphn2 heterophilic reciprocal repulsions. Here, we leveraged conditional knockouts to systematically demonstrate that these mechanisms generalize to extended hippocampal networks, including entorhinal cortex and hypothalamus. Cooperation between attraction and repulsion differs depending on the order in which developing axons encounter the attractant and repellent subfields. Strikingly, Ten3 and Lphn2 can serve both as ligands for incoming axons and receptors for their own target selection, within the same neuron; Ten3 can be repulsive or attractive as ligand or receptor. Thus, multifunctionality and repeated use, together with recurrent circuit motifs prevalent in the brain, enable one ligand-receptor pair to instruct target selection of many more neurons.