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.
Kwon
Seok-Kyu
SK
National Creative Research Initiative Center for Synaptogenesis, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701.
Woo
Jooyeon
J
Kim
Soo-Young
SY
Kim
Hyun
H
Kim
Eunjoon
E
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