LAR-RPTPs Directly Interact with Neurexins to Coordinate Bidirectional Assembly of Molecular Machineries

Neurexins (Nrxns) and LAR-RPTPs (leukocyte common antigen-related protein tyrosine phosphatases) are presynaptic adhesion proteins responsible for organizing presynaptic machineries through interactions with nonoverlapping extracellular ligands. Here, we report that two members of the LAR-RPTP family, PTP sigma and PTP delta, are required for the presynaptogenic activity of Nrxns. Intriguingly, Nrxn1 and PTP sigma require distinct sets of intracellular proteins for the assembly of specific presynaptic terminals. In addition, Nrxn1 alpha showed robust heparan sulfate (HS)-dependent, high-affinity interactions with Ig domains of PTP sigma that were regulated by the splicing status of PTP sigma. Furthermore, Nrxn1 alpha WT, but not a Nrxn1 alpha mutant lacking HS moieties (Nrxn1 alpha Delta HS), inhibited postsynapse-inducing activity of PTP sigma at excitatory, but not inhibitory, synapses. Similarly, cis expression of Nrxnla WT, but not Nrxn1 alpha AHS, suppressed the PTP alpha-mediated maintenance of excitatory postsynaptic specializations in mouse cultured hippocampal neurons. Lastly, genetics analyses using male or female Drosophila Dlar and Dnrx mutant larvae identified epistatic interactions that control synapse formation and synaptic transmission at neuromuscular junctions. Our results suggest a novel synaptogenesis model whereby different presynaptic adhesion molecules combine with distinct regulatory codes to orchestrate specific synaptic adhesion pathways.