| First Author | Han KA | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 44 | Pages | 8438-8462 |
| PubMed ID | 33037075 | Mgi Jnum | J:301621 |
| Mgi Id | MGI:6471260 | Doi | 10.1523/JNEUROSCI.1091-20.2020 |
| Citation | Han KA, et al. (2020) LAR-RPTPs Directly Interact with Neurexins to Coordinate Bidirectional Assembly of Molecular Machineries. J Neurosci 40(44):8438-8462 |
| abstractText | 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, PTPsigma and PTPdelta, are required for the presynaptogenic activity of Nrxns. Intriguingly, Nrxn1 and PTPsigma require distinct sets of intracellular proteins for the assembly of specific presynaptic terminals. In addition, Nrxn1alpha showed robust heparan sulfate (HS)-dependent, high-affinity interactions with Ig domains of PTPsigma that were regulated by the splicing status of PTPsigma. Furthermore, Nrxn1alpha WT, but not a Nrxn1alpha mutant lacking HS moieties (Nrxn1alpha DeltaHS), inhibited postsynapse-inducing activity of PTPsigma at excitatory, but not inhibitory, synapses. Similarly, cis expression of Nrxn1alpha WT, but not Nrxn1alpha DeltaHS, suppressed the PTPsigma-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.SIGNIFICANCE STATEMENT We provide evidence supporting the physical interactions of neurexins with leukocyte common-antigen related receptor tyrosine phosphatases (LAR-RPTPs). The availability of heparan sulfates and alternative splicing of LAR-RPTPs regulate the binding affinity of these interactions. A set of intracellular presynaptic proteins is involved in common for Nrxn- and LAR-RPTP-mediated presynaptic assembly. PTPsigma triggers glutamatergic and GABAergic postsynaptic differentiation in an alternative splicing-dependent manner, whereas Nrxn1alpha induces GABAergic postsynaptic differentiation in an alternative splicing-independent manner. Strikingly, Nrxn1alpha inhibits the glutamatergic postsynapse-inducing activity of PTPsigma, suggesting that PTPsigma and Nrxn1alpha might control recruitment of a different pool of postsynaptic machinery. Drosophila orthologs of Nrxns and LAR-RPTPs mediate epistatic interactions in controlling synapse structure and strength at neuromuscular junctions, underscoring the physiological significance in vivo. |
