Postsynaptic TrkC and Presynaptic PTPσ Function as a Bidirectional Excitatory Synaptic Organizing Complex

Abstract

SUMMARY 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 non-catalytic isoforms suggesting additional functions. Here we discovered non-catalytic 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 PTPσ tyrosine phosphatase receptor. 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.

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

“…Recent studies have established that a host of neuronal transmembrane proteins containing LRR domains play important roles in synapse development, although the precise functions of these proteins are only slowly being uncovered (3,13,17,20,(25)(26)(27). Six Slitrk family members (Slitrk1-6) share similar domain organizations and have been shown to regulate neurite outgrowth in Pheochromocytoma Cell Line 12 (PC12) cells (5,28).…”

“…LAR-RPTP family members are evolutionarily conserved and are functionally required for axon guidance and synapse formation (15). Recent studies have shown that netrin-G ligand-3 (NGL-3), neurotrophin receptor tyrosine kinase C (TrkC), and IL-1 receptor accessory protein-like 1 (IL1RAPL1) bind to all three LAR-RPTP family members or distinct members of the family; however, the functional significance of these multifaceted interactions remains elusive (16)(17)(18).…”

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…A systematic bioinformatics study has shown that extracellular LRR domain-containing proteins have greatly expanded in mammals (135 in mouse, 139 in human) compared with worms (29 extracellular LRR proteins) and flies (66 extracellular LRR proteins) (Dolan et al, 2007). The ligands of these extracellular LRR proteins remain largely unknown, although the process of ligand identification has recently accelerated (de Wit et al, 2009;Ko et al, 2009;Siddiqui et al, 2010;Takahashi et al, 2011;Woo et al, 2009). Mounting evidence from invertebrate systems shows that extracellular LRR proteins control key phases of neuron development and neural circuit formation including axon guidance, target-cell recognition, and synapse formation.…”

“…Inhibitory synapse formation (Slitrk3) (Takahashi et al, 2012) TrkC PTPσ (in vitro) Excitatory synapse formation (Takahashi et al, 2011…”

“…Among the factors that regulate the development of neural circuits, proteins containing extracellular leucine-rich repeat (LRR) domains have recently emerged as key organizers of connectivity (de Wit et al, 2011;Ko and Kim, 2007). Artificial synapse formation assays have shown that a host of LRR-containing proteins, which are widely and highly expressed in the brain, are capable of recruiting various synaptic scaffolds and inducing synaptic differentiation in heterologous cells in which these LRR-containing proteins are exogenously expressed (de Wit et al, 2009;Kim et al, 2006;Ko et al, 2006;Linhoff et al, 2009;Mah et al, 2010;Takahashi et al, 2011;Woo et al, 2009). Selected LRR proteins that function at synapses are shown in Fig.…”