Emerging roles of the neurotrophin receptor TrkC in synapse organization

Abstract

Tropomyosin-receptor-kinase (Trk) receptors have been extensively studied for their roles in kinase-dependent signaling cascades in nervous system development. Synapse organization is coordinated by trans-synaptic interactions of various cell adhesion proteins, a representative example of which is the neurexin-neuroligin complex. Recently, a novel role for TrkC as a synapse organizing protein has been established. Post-synaptic TrkC binds to pre-synaptic type-IIa receptor-type protein tyrosine phosphatase sigma (PTPσ). TrkC-PTPσ specifically induces excitatory synapses in a kinase domain-independent manner. TrkC has distinct extracellular domains for PTPσ- and NT-3-binding and thus may bind both ligands simultaneously. Indeed, NT-3 enhances the TrkC-PTPσ interaction, thus facilitating synapse induction at the pre-synaptic side and increasing pre-synaptic vesicle recycling in a kinase-independent fashion. A crystal structure study has revealed the detailed structure of the TrkC-PTPσ complex as well as competitive modulation of TrkC-mediated synaptogenesis by heparan sulfate proteoglycans (HSPGs), which bind the same domain of TrkC as PTPσ. Thus, there is strong evidence supporting a role for the TrkC-PTPσ complex in mechanisms underlying the fine turning of neural connectivity. Furthermore, disruption of the TrkC-PTPσ complex may be the underlying cause of certain psychiatric disorders caused by mutations in the gene encoding TrkC (NTRK3), supporting its role in cognitive functions.

Keywords: Fibroblast-neuron co-culture; Neuropsychiatric disorders; Neurotrophin-3; PTPσ; Synapse competition; Synapse organizer; Synaptogenesis; TrkC.