Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex.
Neurotrophin receptor tyrosine kinases (Trks) have well-defined trophic roles in nervous system development through kinase activation by neurotrophins. Yet Trks have typical cell-adhesion domains and express noncatalytic isoforms, suggesting additional functions. Here we discovered noncatalytic TrkC in an unbiased hippocampal neuron-fibroblast coculture screen for proteins that trigger differentiation of neurotransmitter release sites in axons. All TrkC isoforms, but not TrkA or TrkB, function directly in excitatory glutamatergic synaptic adhesion by neurotrophin-independent high-affinity trans binding to axonal protein tyrosine phosphatase receptor PTPσ. PTPσ triggers and TrkC mediates clustering of postsynaptic molecules in dendrites, indicating bidirectional synaptic organizing functions. Effects of a TrkC-neutralizing antibody that blocks TrkC-PTPσ interaction and TrkC knockdown in culture and in vivo reveal essential roles of TrkC-PTPσ in glutamatergic synapse formation. Thus, postsynaptic TrkC trans interaction with presynaptic PTPσ generates bidirectional adhesion and recruitment essential for excitatory synapse development and positions these signaling molecules at the center of synaptic pathways.
Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada.
Hideto
H
Takahashi
Pamela
P
Arstikaitis
Tuhina
T
Prasad
Thomas E
TE
Bartlett
Yu Tian
YT
Wang
Timothy H
TH
Murphy
Ann Marie
AM
Craig
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D057907:Post-Synaptic Density / Q000378:metabolism* / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
D011993:Recombinant Fusion Proteins; D018698:Glutamic Acid; D020812:Receptor, trkC; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
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