%0 Journal Article %A Daniel T. Pederick %A Jan H. Lui %A Ellen C. Gingrich %A Chuanyun Xu %A Yuanyuan Liu %A Zhigang He %A Stephen R. Quake %A Liqun Luo %T Latrophilin-2 repels Teneurin-3+ hippocampal axons during target selection %D 2020 %R 10.1101/2020.05.28.122242 %J bioRxiv %P 2020.05.28.122242 %X Spatial- and object-related signals are preferentially processed through the medial and lateral hippocampal networks (MHN and LHN), respectively1,2. MHN comprises interconnected medial entorhinal cortex, proximal CA1 (pCA1), and distal subiculum (dSub), whereas the LHN comprises interconnected lateral entorhinal cortex, distal CA1, and proximal subiculum3,4. Previously, we showed that Teneurin-3 (Ten3) has matching expression in all interconnected regions of the MHN and is required in both CA1 and subiculum for the precise pCA1→dSub axon targeting through homophilic attraction5. Can matching gene expression in interconnected nodes of the LHN also contribute to hippocampal network assembly? Here, we discovered that latrophilin-2 (Lphn2), an adhesion GPCR known to bind teneurins6–8, has matching expression in the LHN that is complementary to Ten3. Viral-genetic perturbations in vivo revealed that Ten3+ pCA1 axons are repelled by ectopic expression of Lphn2 in dSub, and ectopically invade proximal subiculum deleted for Lphn2. Simultaneous subiculum deletion of Lphn2 and Ten3 causes Ten3+ pCA1 axon mistargeting reflecting loss of both repulsion and attraction. Our findings demonstrate that Lphn2 acts as a repulsive ligand for Ten3+ axons, identify Ten3 as a receptor for both repulsive and attractive ligands in the same axon during target choice, and reveal how a ‘Ten3→Ten3, Lphn2→Lphn2’ rule directs the precise assembly of functional hippocampal networks.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2020/05/29/2020.05.28.122242.full.pdf