| 2012 |
Slitrk3 acts as a postsynaptic adhesion molecule that selectively induces inhibitory (GABAergic) presynaptic differentiation via trans-synaptic interaction with axonal PTPδ (receptor protein tyrosine phosphatase delta). When expressed in fibroblasts, Slitrk3 triggered only inhibitory presynaptic differentiation in contacting axons of co-cultured hippocampal neurons. Recombinant Slitrk3 preferentially localized to inhibitory postsynaptic sites. Slitrk3-deficient mice showed decreased inhibitory synapse number and function in hippocampal CA1 neurons and increased seizure susceptibility. |
Heterologous cell synaptogenesis assay (fibroblast co-culture), recombinant protein localization, Slitrk3 knockout mouse analysis (electrophysiology, immunostaining, EEG), trans-interaction assay with PTPδ |
Nature neuroscience |
High |
22286174
|
| 2017 |
Slitrk3 (ST3) interacts with Neuroligin 2 (NL2) through their extracellular domains with nanomolar affinity in a cis interaction. During neuronal maturation, both NL2 and ST3 are required together for inhibitory synapse development; selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development, disrupts hippocampal network activity, and increases seizure susceptibility. NL2 is required for establishing GABAergic transmission in developing neurons, while mature inhibitory synapse development requires both NL2 and ST3 acting synergistically. |
Co-immunoprecipitation, binding affinity measurements, hippocampal neuron culture with genetic perturbation, electrophysiology, seizure susceptibility assays |
Neuron |
High |
29107521
|
| 2019 |
The conserved tyrosine residue Y969 in the intracellular C-terminus of Slitrk3 is critical for GABAergic synapse development. Overexpression of the Y969A mutant markedly reduced gephyrin puncta density and GABAergic transmission in hippocampal neurons. Wild-type ST3, but not ST3 Y969A, rescued GABAergic transmission deficits in neurons lacking endogenous ST3. The C-terminus is not required for ST3 homo-dimerization or trafficking to the cell surface in heterologous cells. |
Site-directed mutagenesis, overexpression and rescue experiments in hippocampal neurons, electrophysiology, immunostaining for gephyrin puncta, heterologous cell surface trafficking assay |
Frontiers in molecular neuroscience |
High |
31551708
|
| 2021 |
ErbB4 interacts in trans with Slitrk3 through the extracellular RLD domain of ErbB4 to promote inhibitory synapse formation onto pyramidal neurons independently of ErbB4 kinase activity. Deletion of the RLD domain abolished induction of gephyrin and GABAAR α1 puncta by ErbB4. Disruption of the ErbB4-Slitrk3 interaction by secretable RLD decreased inhibitory synapses and impaired GABAergic transmission. |
Co-immunoprecipitation/pulldown of ErbB4 and Slitrk3, heterologous cell co-culture synaptogenesis assay, domain deletion mutants, kinase-dead knock-in mice, electrophysiology |
Translational psychiatry |
High |
34226493
|
| 2021 |
Gephyrin interacts with Slitrk3 as part of the synapse stabilization mechanism downstream of adenosine A2A receptor and GABAAR activation. PKA-mediated phosphorylation of gephyrin on serine 303 is required for GABAAR stabilization, and stabilization of pre- and postsynaptic GABAergic elements involves the gephyrin-Slitrk3 interaction. |
Co-immunoprecipitation of gephyrin and Slitrk3, phosphorylation site mutagenesis (gephyrin S303), pharmacological receptor activation/inhibition, live imaging of synapse stability |
Science (New York, N.Y.) |
Medium |
34735259
|
| 2017 |
LAR-RPTP (PTPδ) binding to Slitrk3 (as well as IL1RAPL1 and IL-1RAcP) induces reciprocal higher-order clustering of trans-synaptic adhesion complexes. Crystal structure of LAR-RPTP/IL1RAPL1 complex reveals lateral interactions critical for higher-order assembly; competitive binding of heparan sulfate to LAR-RPTP can dismantle pre-established LAR-RPTP/Slitrk3 trans-synaptic complexes. |
Crystal structure determination, cell clustering assay, competitive binding with heparan sulfate, synaptogenesis assay in HEK cell co-culture |
Frontiers in molecular neuroscience |
Medium |
29081732
|
| 2003 |
SLITRK3 protein is characterized as an integral membrane protein with two leucine-rich repeat (LRR) domains similar to Slit proteins and a C-terminal domain partially similar to Trk neurotrophin receptors. It is expressed predominantly in the brain. |
Genomic organization analysis, expression profiling (Northern blot/RT-PCR), protein domain characterization |
Gene |
Medium |
14557068
|
| 2024 |
Biallelic loss-of-function variants in SLITRK3 (C566R and E606X) cause epileptic encephalopathy. Patient variants C566R and E606X alter SLITRK3 protein surface expression by causing accumulation in the Golgi apparatus. Primary hippocampal neuron cultures carrying patient variants show reduced GABAergic transmission (confirmed by electrophysiology). SLITRK3 KO mice exhibit spontaneous epileptiform EEG activity, enhanced pentylenetetrazole-induced seizures, increased motor activity, and reduced parvalbumin interneurons. |
Patient-derived neuron cultures, electrophysiology, immunostaining of HEK-293 cells (cell surface vs. Golgi localization), SLITRK3 knockout mouse EEG and behavioral analysis |
Frontiers in molecular neuroscience |
High |
38495551
|
| 2021 |
SLITRK3 gene amplification in lung squamous cell carcinoma (LUSC) leads to SLITRK3-dependent activation of NTRK3 (TrkC), promoting a cancer stem cell phenotype. SLITRK3-dependent NTRK3 activation was demonstrated by sphere-formation assay and CD133-positive cell fraction analysis, and was inhibited by NTRK-targeted inhibitors. |
In situ immunofluorescence, sphere-formation assay, FACS analysis of CD133+ fraction, pharmacological inhibition of NTRK in LUSC cell lines |
Molecular biomedicine |
Low |
35006496
|