Trans-synaptic adhesions between netrin-G ligand-3 (NGL-3) and receptor tyrosine phosphatases LAR, protein-tyrosine phosphatase delta (PTPdelta), and PTPsigma via specific domains regulate excitatory synapse formation.
Synaptic cell adhesion molecules regulate various steps of synapse formation. The trans-synaptic adhesion between postsynaptic NGL-3 (for netrin-G ligand-3) and presynaptic LAR (for leukocyte antigen-related) regulates excitatory synapse formation in a bidirectional manner. However, little is known about the molecular details of the NGL-3-LAR adhesion and whether two additional LAR family proteins, protein-tyrosine phosphatase delta (PTPdelta), and PTPsigma, also interact with NGL-3 and are involved in synapse formation. We report here that the leucine-rich repeat (LRR) domain of NGL-3, containing nine LRRs, interacts with the first two fibronectin III (FNIII) domains of LAR to induce bidirectional synapse formation. Moreover, Gln-96 in the first LRR motif of NGL-3 is critical for LAR binding and induction of presynaptic differentiation. PTPdelta and PTPsigma also interact with NGL-3 via their first two FNIII domains. These two interactions promote synapse formation in a different manner; the PTPsigma-NGL-3 interaction promotes synapse formation in a bidirectional manner, whereas the PTPdelta-NGL-3 interaction instructs only presynaptic differentiation in a unidirectional manner. mRNAs encoding LAR family proteins display overlapping and differential expression patterns in various brain regions. These results suggest that trans-synaptic adhesion between NGL-3 and the three LAR family proteins regulates excitatory synapse formation in shared and distinct neural circuits.
National Creative Research Initiative Center for Synaptogenesis, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701.
Seok-Kyu
SK
Kwon
Jooyeon
J
Woo
Soo-Young
SY
Kim
Hyun
H
Kim
Eunjoon
E
Kim
D000818:Animals; D001921:Brain / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D007739:L Cells; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
C549573:Lrrc4b protein, rat; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C516772:PTPRF protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2