Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions (original) (raw)
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Slitrk1 is localized to excitatory synapses and promotes their development
Scientific reports, 2016
Following the migration of the axonal growth cone to its target area, the initial axo-dendritic contact needs to be transformed into a functional synapse. This multi-step process relies on overlapping but distinct combinations of molecules that confer synaptic identity. Slitrk molecules are transmembrane proteins that are highly expressed in the central nervous system. We found that two members of the Slitrk family, Slitrk1 and Slitrk2, can regulate synapse formation between hippocampal neurons. Slitrk1 is enriched in postsynaptic fractions and is localized to excitatory synapses. Overexpression of Slitrk1 and Slitrk2 in hippocampal neurons increased the number of synaptic contacts on these neurons. Furthermore, decreased expression of Slitrk1 in hippocampal neurons led to a reduction in the number of excitatory, but not inhibitory, synapses formed in hippocampal neuron cultures. In addition, we demonstrate that different leucine rich repeat domains of the extracellular region of Sl...
Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction
Nature Neuroscience, 2012
Balanced development of excitatory and inhibitory synapses is required for normal brain function, and their imbalance may underlie pathogenesis of neuropsychiatric disorders. Compared with many identified trans-synaptic adhesion complexes that organize excitatory synapses, little is known about organizers specific for inhibitory synapses. Here we report Slit and NTRK-like family member 3 (Slitrk3) as a postsynaptic adhesion molecule that selectively regulates inhibitory synapse development via trans-interaction with axonal tyrosine phosphatase receptor PTPδ. Slitrk3 expressed in fibroblasts triggers only inhibitory presynaptic differentiation in contacting axons of cocultured rat hippocampal neurons. Recombinant Slitrk3 preferentially localizes to inhibitory postsynaptic sites. Slitrk3-deficient mice exhibit decreases in inhibitory but not excitatory synapse number and function in hippocampal CA1 neurons and exhibit increased seizure susceptibility and spontaneous epileptiform activity. Slitrk3 requires trans-interaction with Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion
Nature Communications, 2014
Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit-and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structureguided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.
Proceedings of the National Academy of Sciences, 2013
The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit-and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.
Recruitment of scribble to the synaptic scaffolding complex requires GUK-holder
2002
In particular, membrane-associated guanylate kinases University of Massachusetts (MAGUKs), such as PSD-95, have emerged as central Amherst, Massachusetts 01003 elements in the formation of heteromultimeric scaffolds 2 Department of Neurochemistry underneath the membranes of glutamatergic synapses Leibniz Institute for Neurobiology in both vertebrates and invertebrates. At the mammalian Brenneckestrasse 6 postsynaptic density, MAGUKs can bind ionotropic glu-39118 Magdeburg tamate receptors [3-5], components of second messen-Germany ger cascades [6, 7], and cell adhesion molecules [8] via 3 Department of Genetics their PDZ and SH3 domains. Similarly, at insect neuro-Harvard Medical School muscular junctions (NMJs), the PSD-95 ortholog DLG HHMI can concurrently bind a cell adhesion molecule (Fas-Boston, Massachusetts 02115 ciclin II [FasII]) [9] and a Shaker K ϩ channel [10]. Such arrangements may contribute to the functional coupling of the respective MAGUK binding partners. For example, simultaneous binding of NMDA receptors and a synaptic Summary Ras-GTPase activating protein (SynGAP) to PSD-95 could allow for the cooperative coupling of synaptic Background: Membrane-associated guanylate kinases activity and Ras-mediated signaling pathways [6]. (MAGUKs), such as Discs-Large (DLG), play critical roles While the PDZ and SH3 domains of MAGUKs are in synapse maturation by regulating the assembly of known to bind components required for synapse funcsynaptic multiprotein complexes. Previous studies have tion, the significance of the guanylate kinase-like (GUK) revealed a genetic interaction between DLG and another domain has remained puzzling. Several studies suggest PDZ scaffolding protein, SCRIBBLE (SCRIB), during the that it might act as a protein interaction domain. For establishment of cell polarity in developing epithelia. A example, in mammals, this domain binds to GKAP/ possible interaction between DLG and SCRIB at synap-SAPAPs [11, 12], which are in turn linked to Shank/ tic junctions has not yet been addressed. Likewise, the ProSAP [13, 14]. It has also been reported to bind biochemical nature of this interaction remains elusive, MAP1A [15] to a kinesin-like protein [16], to SPAR, an raising questions regarding the mechanisms by which actin cytoskeleton regulator [17], and to interact intrathe actions of both proteins are coordinated. molecularly with the SH3 domain [18-20]. In Drosophila, dlg mutants in which the GUK domain Results: Here we report the
Neuron, 2017
In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reve...