1. Introduction
Construction of the neural netwoks depends largely on precise contacts between neurons and non-neuronal cells. Numerous studies have described different types of adhesive interactions between cells in the nervous system. These include adhesive contacts between neural cell bodies, axonal attachments to glial cells, axon fasciculation, connection between pre- and postsynaptic specializations as well as to cells outside the nervous system. Although some of the molecules that mediate each of these types of neural adhesive contacts have been characterized, some remain unknown.
Neuronal synapses can be considered as a specialized type of cell-cell interaction that mediates communication between neurons and their target cells. It involves the interaction between two asymmetric partners, the presynaptic specialization, where the synaptic vesicles release neurotransmitters and the postsynaptic density, which contains receptors and adapter scaffold proteins that transduce the neurotransmitter signal [1].As at other cell-cell junctions, such as epithelial tight junctions or the immune synapse, synaptically-localized neural cell adhesion molecules are not merely static structural components but are often dynamic regulators of synapse function.
In the last years numerous studies provide new insights into the role of adhesion molecules in the formation, maturation, maintenance, function and plasticity of synaptic contacts. Several cell adhesion molecules have been involved in synapse development, including, cadherins, proteocadherins, integrins, NCAM, L1, Fasciclina, Syg, Sidekicks, SynCam, Neurexin-Neuroligin, LRRTM, GDNF/GFR, Neurexin/Cbl1/GluR2, between others [2].
During neuronal development, specific synaptic circuits are generated by synapse formation between the appropriate pre- and postsynaptic partners and aberrant connectivity can lead to nervous system disorders. The accuracy of synapse formation is fundamental for the normal brain development and depends in part on the controlled spatial and temporal expression of selective adhesion molecules on neuronal surface.
2. Adhesion at the synapses
Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre- and postsynaptic specializations but do far more than simply provide a mechanical link between cells, they are important elements in the
2.1. Neurexins and neuroligins
Neurexins (Nrxns) and Neuroligins (Nlgns) are the best characterized synaptic cell adhesion system.Neurexins were originally discovered as receptors for -latrotoxin, a vertebrate-specific toxin present in the black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release [5]. There are two types of Nrxns, a longer -Nrxn (-Nrxn and a shorter -Nrnx (-Nrxn isoforms. While -Nrxn have six extracellular LNS domains (Laminin/ Neurexin/ Sex hormone-binding globulin-domain) with three intercalated EGF-like domains, -Nrxn only contains a single LNS domain [6,7,8]. Immunofluorescence and subcellular fractionation analysis indicate that Nrxns are located on presynaptic terminals [6,9].
Mammals contain three Nrxn genes (Nrxn1-3), each of which directs the transcription of - and -Nrxns from independent promoters [10]. Neurexins are evolutionary conserved and pan-neuronally expressed [10,11]. Homologues of neurexin genes have been described in low vertebrates such as
Neuroligins have been identified as endogenous Nrxns ligands [19,20]. As Nrxns, Neuroligins (Nlgns) are type I membrane proteins that consist of an extracellular region, involved in
Nrxn-Nlgn complex has been involved in the formation, maturation and function of vertebrate synapses. The evidence indicates that Nrxn-Nlgn bind each other by their extracellular domain to promote adhesion between pre- and postsynaptic specializations, recruiting pre- and postsynaptic molecules to form a functional synapse. Cell based assays of synapse assembly showed that contact of dissociated neurons with Nlgn-expressing fibroblasts can induce the formation of functional presynaptic specializations by recruiting components of the presynaptic machinery in co-cultured neurons [32], while contact of neurons with Nrxn expressing non-neuronal cells can induce postsynaptic differentiation and clustering of postsynaptic receptors in contacting dendrites [31,33].
Recent studies indicate that alternative splicing of
The
Although the
2.2. LRRTM
The LRRTM gene family was first described in 2003 [45]. The LRRTM family has four members (LRRTM 1-4) that share similar domain structure with an extracellular domain containing ten extracellular leucine-rich repeats that mediate protein-protein interactions, followed by a single transmembrane domain and a short c-terminal sequence containing a class I PDZ-domain-binding motif. Human and mouse LRRTMs are highly conserved and orthologous genes exist in other vertebrates, but not in invertebrates [45].
All four LRRTMs family members are post-synaptic localized and when expressed in non-neuronal cells co-cultured with hippocampal neurons they can induce presynaptic differentiation in contacting axons. LRRTM1 and LRRTM2 selectively promote excitatory, but not inhibitory presynaptic differentiation [46]. In addition, Wit et al (2009) demonstrated that LRRTM2 can interact with the post-synaptic protein PSD-95 and regulate surface expression of AMPA receptors [48].
Independent studies have shown that post-synaptic LRRTM1 and LRRTM2 bind specifically to presynaptic and -Nrxn lacking an insert at S4 [49]. Thus, whereas Nlgns bind Nrxn containing or lacking an insert in splice site S4, LRRTMs bind only Nrxns lacking an insert in this splicing site [48,50]. This ability to regulate interaction Nrxn-Nlgn and Nrxn-LRRTM provides an intringuing mechanism for regulating synaptic specificity.
Consistent with the effects of LRRTM on neuronal connectivity, deletion of LRRTM1 in mice revealed altered distribution of the vesicular glutamate transporter vGlut1
2.3. SynCAM
The SynCAM (Synaptic Cell Adhesion Molecule) family comprises four genes encoding proteins (SynCAM1-4) with three inmuonoglobulin (Ig)-like domains, a single transmembrane region, and a short cytosolic tail with a PDZ type II motif. SynCAM proteins are predominantly expressed in the brain and localize to pre- and postsynaptic sites [52,53].
All SynCAMs are expressed mostly by neurons during the peak period of synaptogenesis around the second postnatal week and remains expressed throughout adulthood in the hippocampus [52].
SynCAM proteins are present at presynaptic and postsynaptic specializations and are involved in homophilic and heterophilic interactions via the extracellular (Ig)-like domains. Interestingly, SynCAM1, 2 and 3, but not SynCAM4, can associate
3. Control of synapse formation by ligand-induced cell adhesion molecules (LICAM)
During the last years, a novel mechanism of ligand-induced cell adhesion has been described. Unlike other cell adhesion systems, which involve the simple encounter of membrane associated cell adhesion molecules
3.1. GDNF and GFR1
The Glial cell-line Derived Neurotrophic Factor (GDNF) and its glycosylphosphatidylinositol (GPI)-anchor receptor, GFR1, represent the first example of this new mechanism of cell-adhesion [56]. In this system, GDNF, is able to mediate
During the last years, numerous studies have shown that GDNF-family ligands contribute to synapse development and maturation [57,58]. The developmental expression pattern of GFR1 and its ligand, GDNF, during the period of hippocampal synaptogenesis as well as its subcellular localization at pre- and postsynaptic specializations indicated a possible role of GDNF-GFR1 complex in the formation of neuronal synapses by inducing
3.2. Cerebelin-GluR-neurexin
More recently another example of ligand-induced
Based on its amino acid sequence, GluR2, is a member of the ionotrophic glutamate receptor family, which plays an essential role in cerebellar Purkinje cells (PC) synapse formation [61,62]. The synaptogenic activity induced by GluR2 can be reproduced
The evidence indicates that Cbln1 interacts with different subtypes of -Nrxn and -Nrxn containing the S4 insert, but not to subtypes lacking the S4 insert, to induce synaptogenesis in cultured cerebellar, hippocampal and cortical neurons. Interestingly, -Nrxn containing the S4 insert binds to Cbln1 [62] but does not bind to any Nlgs or LRRTMs. Another distinctive feature of the Nrxn/Cbln1/GluR2 complex is that it is insensitive to the extracellular Ca2+ concentration [62]; while binding of Nrxn to Nlgs and LRRTMs requires extracellular Ca2+.
While GluR2 is mainly expressed in cerebellar Purkinje cells, GluR1 is widely expressed in the developing forebrain including the caudate putamen and hippocampus. In a recent study it has been demonstrated that, in the presence of Cbln1 or Cbln2, GluR1 expressed in non-neuronal cells can induce inhibitory presynaptic differentiation on cultured cortical neurons by interacting with Nrxns containing the S4 insert [64].
4. Transient cell-cell interactions in neural development
The majority of
Ligand-induced cell adhesion represents a new way to regulate intercellular interactions that may have broad implications not only for the development of the nervous system, but also in other tissues and organs.
5. Role of synaptic cell adhesion systems in nervous system disorders
The ability of
Numerous studies indicate a genetic link of mutations in synaptic cell adhesion molecules to autism-spectrum disorders (ASD), in particular to Nlgs and Nrxns [72,73]. Mutations in genes encoding Nrxn1, Nlg3 and Nlg4 have been described to be associated with ASD. These alterations include different type of mutations that have been observed in a small fraction of patients. In particular thirteen different mutations have been described in
The role of some of these proteins in ASD has been validated in trasgenic animals. Thus, the Nlg3-R451C knockin mouse were reported to show a phenotype that shares some, but not all features with human ASD patients These mice show a modest impairment in social behaviour [89]. Moreover, Nlg-4 knockout mice show deficits in social interactions and communication [90].
In addition, members of SynCAM and LRRTM families have also been associated with nervous system disorders. SynCAM1 has been associated with ASD. Two missense mutations in the SynCAM1 gene of ASD patients and their families have been described.Interestingly, the mutations were located in one domain, which is essential for trans-synaptic interaction [91]. In a recent genetic study, polymorphisms in LRRTM3 were associated with ASD [88]. Moreover, LRRTM1 has been associated with schizophrenia [92].
There is no strong evidence connecting mutations in genes involved in ligand-induced cell adhesion systems with nervous system diseases. So far, only GluR1 was found to be associated with schizophrenia [92,93].
Further studies linking mutations in cell adhesion systems with nervous system diseases will contribute to the design of new diagnostic and therapeutic tools for these disorders.
6. Perspectives
It is well established, that cell-adhesion systems are in part responsible for the construction of neural circuits, synapse formation and plasticity. The correct function of the nervous system depends on the establishment of precise synaptic contacts between neurons and its specific targets, and deficits in genes coding for
During the last years several adhesion molecules have been reported to participate in synapse development, including integrins, cadherins, protocadherins, NCAM, Neurexin-Neuroligin, LRRTM, SynCam, GDNF/GFR, Nrxn-Cbl1-GluR2. The discovery of alternative
Based on this, the main challenge will be now to elucidate the complex code by which the
It will be also necessary to address whether individual synapse organizing protein instruct synaptic cell adhesion, or if the
The fact that multiple partners function at the same synapses opens the possibility that they cooperate in the recruitment of the same components to the synapse. Indeed, it has been described that overexpression of Nlgns and LRRTMs in primary hippocampal neurons cooperate in a synergistic manner in glutamate synapse development visualized by an increase in the recruitment of pre-synaptic proteins. Cooperation between different adhesion systems may help to stabilize interactions across the cleft by recruiting the pre- and postsynaptic machinery at multiple points. However the existence of mechanisms that can modulate and modify these interactions should be important, especially for synaptic plasticity.
Further understanding of the molecular pathways and circuit events downstream these cell adhesion organizing systems will be extremely important in light of the role of trans-synaptic cell adhesion molecules in neurodevelopmental and cognitive diseases.
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