TY - JOUR TI - Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons AU - Pederick, Daniel T AU - Perry-Hauser, Nicole A AU - Meng, Huyan AU - He, Zhigang AU - Javitch, Jonathan A AU - Luo, Liqun A2 - Monk, Kelly A2 - Bronner, Marianne E A2 - Zou, Yimin VL - 12 PY - 2023 DA - 2023/03/20 SP - e83529 C1 - eLife 2023;12:e83529 DO - 10.7554/eLife.83529 UR - https://doi.org/10.7554/eLife.83529 AB - The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a repulsive receptor in distal CA1 neurons to direct their axons to the proximal subiculum, and as a repulsive ligand in the proximal subiculum to direct proximal CA1 axons to the distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to Gα12/13 in heterologous cells; this coupling is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2’s tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site alone prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to the proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor in axons. By contrast, neither tethered agonist activity nor autoproteolysis were necessary for Lphn2’s role as a repulsive ligand in the subiculum target neurons. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner. KW - neuronal circuit assembly KW - G protein signaling KW - latrophilin JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -