Cell-cell communications in neural circuit assembly

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PROJECT SUMMARY A key question in neurobiology is how individual neurons precisely connect with each other to form functional circuits during development. Understanding the mechanisms of neural circuit assembly in the mammalian brain may provide insights into the etiology of human brain disorders. In the mammalian brain, each neuron on average forms connection with thousands of other neurons. The assembly of these complex circuits depends on cell-cell communication during many steps of neural development. In the previous three cycles of this grant, we have developed methods such as MADM (Mosaic Analysis with Double Markers) and viral-genetic manipulations in mice that allowed us to label and genetically manipulate specific neuron cell types, down to individual neurons, and study genes that play key roles in dendrite morphogenesis and target selection of axons. Specifically, we have recently identified two cell-surface proteins, Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2), that are expressed in complementary patterns in the interconnected nodes of hippocampal network, following a “Ten3→Ten3, Lphn2→Lphn2” connectivity rule . We have shown that Lphn2 acts as a heterophilic repulsive ligand and Ten3 acts as a homophilic attractive ligand to direct Ten3+ proximal CA1 axons to selectively target to distal subiculum; at the same time, Ten3 acts as a repulsive ligand to direct Lphn2+ axons to proximal subiculum. We have also developed a method that allows us to profile cell-surface proteomes with exquisite sensitivity and spatiotemporal control. In this proposal, we will expand on both of these recent advances. Specifically, we will investigate whether Ten3 and Lphn2 instruct wiring specificity in multiple nodes of the extended hippocampal network and in other brain regions, how Ten3-Lphn2 interaction leads to axon repulsion, and whether G protein signaling is essential for Lphn2’s action as a receptor or a ligand. Complementary to the in-depth studies of Ten3 and Lphn2, we will use our cell-surface proteomic profiling methods to broadly survey changes of cell- surface proteomes from developing to mature neurons, and to identify new cell-surface proteins that regulate dendrite morphogenesis and neural circuit assembly.