Trends in Neurosciences
Feature ReviewSpecial Issue: Circuit Development and RemodelingControl of neural circuit formation by leucine-rich repeat proteins
Section snippets
LRR proteins and the organization of functional neural circuits
The function of neural circuits depends on the precise connectivity between populations of neurons. In the central nervous system (CNS) this is mediated by glutamatergic and GABAergic synapses, and there is emerging evidence that disruptions in the formation or function of excitatory or inhibitory synapses lead to excitation/inhibition (E/I) imbalances, which characterize several psychiatric and neurodevelopmental disorders 1, 2, 3, 4, 5, 6, 7, 8. These considerations underscore the importance
LRR proteins as regulators of synapse development
Recent studies have identified several closely related LRR protein families as regulators of synapse development. A simple in vitro assay, which tests the ability of neurons to form synapses onto co-cultured heterologous cells expressing candidate genes 10, 11, has been instrumental in identifying synapse-organizing or synaptogenic LRR proteins. The elucidation of their trans-synaptic interactions has highlighted a common theme of diverse postsynaptic ligands coupling to a limited repertoire of
LRR transmembrane neuronal proteins control excitatory synapse development via distinct presynaptic partners
Since their original identification as synaptogenic proteins in a co-culture assay-based expression screen [12], LRR transmembrane neuronal proteins (LRRTMs) 1–4 have rapidly become the most intensively studied family of LRR-containing synaptic organizers. LRRTMs are type I transmembrane proteins with an extracellular LRR domain and a C-terminal postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (zo-1) (PDZ) interaction site (
Slit- and Trk-like proteins regulate excitatory and inhibitory synapse development via receptor protein tyrosine phophatases
Based on their structural similarity to LRRTMs (Figure 1B), Slit- and Trk-like proteins (Slitrks) 1–6 were predicted to have synaptogenic properties in a bioinformatics search [12]. When tested in the co-culture assay, Slitrk2 expressed on the surface of fibroblasts indeed induced presynaptic differentiation in contacting axons [12]. Subsequent studies showed that all Slitrk family members have similar activity [28]. Slitrks are broadly expressed in the hippocampus (Figure 4), and are
Netrin-G ligands regulate input-specific synapse development
Netrin-G ligands (NGL)1–3 are structurally related to LRRTMs and Slitrks, but contain an additional Ig domain in their extracellular region (Figure 1C). Their identification as PSD-95 interactors in yeast two hybrid screens suggested a role at synapses, and biochemical fractionation and immuno-EM confirmed that NGL-2 and -3 localize to the postsynaptic density 33, 39. All NGLs induce presynaptic differentiation in co-culture assays, with NGL-3 having markedly stronger effects than NGL-1 or -2 33
Fibronectin leucine-rich repeat transmembrane proteins interact with latrophilin, a presynaptic adhesion GPCR
Similar to LRRTMs, Slitrks, and NGLs, fibronectin leucine-rich repeat transmembrane proteins (FLRT)1–3 bind to a presynaptic receptor that interacts with multiple postsynaptic ligands. In the hippocampus, FLRT2 and FLRT3 show complementary expression patterns (Figure 4), whereas FLRT1 is only weakly expressed. The role of FLRTs in synaptic development is best characterized for FLRT3, an adhesion molecule present at excitatory synapses and in postsynaptic density fractions [52]. Affinity
Other LRR proteins regulating excitatory and inhibitory synapse development
A surprising discovery from a co-culture-based expression screen is TrkC [32], the tyrosine kinase receptor for the neurotrophin NT-3, which broadly regulates neural development [75]. TrkC is the only Trk receptor that induces presynaptic differentiation in co-cultures, and this requires the LRR and first Ig domain, which are not involved in NT-3 binding. TrkC trans-synaptically interacts with RPTPσ, but not with RPTPδ or LAR, and this interaction is required for excitatory synapse development,
LRR proteins as regulators of synaptic function and plasticity
The LRR proteins discussed thus far all have synaptogenic effects in cultured neurons. An exception is Elfn1, an LRR protein with a domain organization similar to FLRTs, but containing a longer cytoplasmic tail. Elfn1 does not induce presynaptic differentiation in co-culture assays or affect synapse number when overexpressed in cultured neurons [81]. Rather, Elfn1 trans-synaptically instructs presynaptic neurotransmitter release properties. Elfn1 is expressed in somatostatin-positive
Concluding remarks
There has been tremendous progress in the past few years in the identification of novel LRR-containing synaptic adhesion molecules, the elucidation of their trans-synaptic interactions, and the understanding of their role in the development and plasticity of synapses. Several families of postsynaptic LRR proteins, with similar domain organization, but with distinct cell type-specific expression, have now been identified. The significance of such diversity of LRR proteins, especially at
Acknowledgments
Work in the authors’ labs on LRR proteins is supported by an ERC Starting Grant (#311083) and FWO Odysseus Grant (J.d.W.), and NIH grant R01NS067216 (A.G.).
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Spinal caspase-3 contributes to tibial fracture-associated postoperative allodynia via up-regulation of LRRTM1 expression in mice
2020, Neuroscience LettersCitation Excerpt :Given an important role of AMPAR in chronic pain-related syndromes [4,16–18], we investigated whether and how spinal caspase-3 mediates fracture-associated postoperative pain. Leucine-rich repeat transmembrane proteins (LRRTMs) are synaptic cell adhesion molecules that drive excitatory synapse formation as well as affect synaptic function [19,20]. LRRTM1 has been recognized for its prominent role in the maintenance of AMPAR density at synapses and long-term potentiation (LTP) [21,22].
Identification of MAGUK scaffold proteins as intracellular binding partners of synaptic adhesion protein Slitrk2
2020, Molecular and Cellular NeuroscienceAMIGO2 Scales Dendrite Arbors in the Retina
2019, Cell ReportsSynaptic organizers: synaptic adhesion-like molecules (SALMs)
2019, Current Opinion in Structural BiologyCitation Excerpt :Furthermore, disrupting SALM5 dimerization impaired its function in inducing presynaptic differentiation [30••,31••]. Besides SALMs, a large number of LRR-containing synaptic adhesion molecules such as the LRRTMs [40], netrin-G ligands (NGLs) [41] and Slitrks [42] have been identified to be involved in synapse formation and maintenance. Recent crystal structure of LRRTM2 in complex with neurexin revealed that the functional unit of LRRTM2 for synaptogenesis is a monomer [43], although SEC-MALLS analysis for LRRTM2 indicated species with a higher than monomer molecular weight [44].