| First Author | Lee SJ | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 13 | Pages | 4688-701 |
| PubMed ID | 22457515 | Mgi Jnum | J:183856 |
| Mgi Id | MGI:5319434 | Doi | 10.1523/JNEUROSCI.5584-11.2012 |
| Citation | Lee SJ, et al. (2012) GluRdelta2 assembles four neurexins into trans-synaptic triad to trigger synapse formation. J Neurosci 32(13):4688-701 |
| abstractText | Elucidation of molecular mechanisms of synapse formation is a prerequisite for the understanding of neural wiring, higher brain functions, and mental disorders. The trans-synaptic interaction of postsynaptic glutamate receptor delta2 (GluRdelta2) and presynaptic neurexins (NRXNs) through cerebellin precursor protein 1 (Cbln1) mediates synapse formation in vivo in the cerebellum. Here, we asked how the trans-synaptic triad induces synapse formation. Native GluRdelta2 existed as a tetramer in the membrane, whereas the N-terminal domain (NTD) of GluRdelta2 formed a stable homodimer. When incubated with cultured mouse cerebellar granule cells (GCs), dimeric GluRdelta2-NTD and Cbln1 exerted little effect on the accumulation of punctate immunostaining signals for Bassoon and vesicular glutamate transporter 1 in GC axons. However, tetramerized GluRdelta2-NTD stimulated the accumulation of these presynaptic proteins in the axons. Analysis of Cbln1 mutants suggested that the binding sites of GluRdelta2 and NRXN1beta on Cbln1 are differential. Furthermore, there was no competition in the binding to Cbln1 between GluRdelta2-NTD and the extracellular domain (ECD) of NRXN1beta. Thus, GluRdelta2 and Cbln1 interacted with each other rather independently of Cbln1-NRXN1beta interaction and vice versa. Gel filtration and isothermal titration calorimetry analyses consistently showed that dimeric GluRdelta2-NTD and hexameric Cbln1 assembled in the 1:1 ratio, whereas hexameric Cbln1 and the laminin-neurexin-sex hormone-binding globulin domain of NRXN1beta-ECD assembled in the 1:2 ratio. Thus, the synaptogenic triad is assembled from tetrameric GluRdelta2, hexameric Cbln1, and monomeric NRXN in the ratio of 1:2:4. These results suggest that GluRdelta2 triggers synapse formation by clustering four NRXNs through triad formation. |
