Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
* Author for correspondence (e-mail: ytakai{at}molbio.med.osaka-u.ac.jp)
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Introduction |
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Synapses |
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Type II cadherins (cadherin-6, cadherin-8 and cadherin-11), which have five EC domains (EC1 to EC5) and do not have an HAV cell adhesion recognition sequence in their EC1 domains, and other type I cadherins (E- and R-cadherins) localize at the synapses with their associated catenins (Yagi and Takeichi, 2000). Multiple cadherins are differentially expressed in the brain; they could function as `lock-and-key' components for regulating specific interneuronal connections.
Protocadherins are cell adhesion molecules that have varying numbers of EC domains but divergent cytoplasmic domains that do not appear to signal through catenins (Wu and Maniatis, 1999; Wu et al., 2001
). Multiple
- and
-protocadherin isoforms are highly expressed in distinct, although partially overlapping, sets of neurons and concentrated at synapses (Kohmura et al., 1998
; Wang et al., 2002
). The complex genomic organization and alternative splicing of the protocadherins has led to speculation that their diversity underlies synaptic specificity (Weiner et al., 2005
).
Several Ig superfamily CAMs (for cell adhesion molecule), which have varying numbers of Ig-like domains, have been identified at synapses and shown to be involved in synaptic plasticity. For example, neural cell adhesion molecule (NCAM), a five Ig-like domain and a two fibronectin type III repeat containing protein, engages in homophilic and heterophilic interactions with a variety of ligands at synapses, such as fibroblast growth factor receptor (FGFR), L1, TAG-1/axonin-1 and heparan sulfate proteoglycans (Walsh and Doherty, 1997; Kiss and Muller, 2001
). NCAM is widely expressed in the developing and adult brains and plays crucial roles in migration of neuronal precursor cells, fasciculation and pathfinding of axons, and synaptic plasticity. It is involved in both early synaptogenesis and subsequent synaptic maturation (Polo-Parada et al., 2001; Dityatev et al., 2004
).
SYG-1/SYG-2 and Sidekick are specific adhesion molecules that determine synaptic specificity in a lock-and-key manner. SYG-1, a four Ig-like-domain-containing protein, and SYG-2, a seven Ig-like-domain and a fibronectin-type-III-repeat-containing protein, were isolated in a genetic screen for C. elegans mutants that exhibit defective synaptic positioning (Shen and Bargmann, 2003; Shen et al., 2004
). SYG1-1 interacts with SYG-2 and induces formation of synapses while suppressing inappropriate synapses. Sidekick, which has six Ig-like domains and thirteen fibronectin type III repeats, has been implicated in selective synapse formation in the chicken retina (Yamagata et al., 2002
).
Since the results in the synaptic localization of SynCAM1 (Biederer et al., 2002) are inconsistent with the results reported by other groups (Wakayama et al., 2001
; Fukami et al., 2002
; Shingai et al., 2003
; Kakunaga et al., 2005
), we do not describe SynCAM1 as a synaptic CAM. SynCAM1 has been shown to be ubiquitously expressed and identical to nectin-like molecule-2 (Necl-2)/IGSF4/RA175/SgIGSF/TSLC1, which is not concentrated at synapses.
Neuroligin, an esterase-like-domain-containing protein on the presynpatic side, interacts with ß-neurexin, a laminin-globular-domain-containing protein on the post-synaptic side, at SJs and induces formation of synapses (Graf et al., 2004; Chih et al., 2005
). However, when, where, and how precisely ß-neurexin and neuroligin induce synaptogenesis remains obscure.
Eph receptor tyrosine kinases and their ephrin ligands are grouped into two families: ephrinA ligands are tethered to the plasma membrane by a glycosyl phosphatidylinositol (GPI) linkage and bind to EphA receptors; whereas ephrinB ligands are transmembrane proteins that bind preferentially to EphB receptors. EphB receptors localize to synapses, where they bind N-methyl-D-aspartate-type glutamate receptors. The typical Eph-ephrin interaction is not an example of classical adhesion, as described above, but rather leads to repulsion. Localized membrane shedding of ephrinB by metalloproteases converts initial adhesion to repulsion.
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Axon-astrocyte contacts |
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Necl-1/TSLL1/SynCAM3, which has a domain structure similar to that of nectins, localizes at axon-astrocyte contacts (Kakunaga et al., 2005). Necl-1 shows Ca2+-independent homophilic cell-cell adhesion activity and heterophilic cell-cell adhesion activity with Necl-2, nectin-1 and nectin-3, but not Necl-5 or nectin-2. It is specifically expressed in neural tissue, where it localizes to contact sites along axons, nerve terminals and glial cell processes that form synapses, axon bundles and myelinated axons.
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Paranodal junctions |
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Axon-axon contacts |
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NCAM is also involved in fasciculation and pathfinding of axons. Poor axonal fasciculation is observed in the hippocampi of NCAM-deficient mice, resulting in impaired synapse formation in the CA3 region (Cremer et al., 1997). This function of NCAM appears to be mediated primarily by its polysialic acid moiety (Monnier et al., 2001
).
BEN/DM-GRASP has five Ig-like domains and mediates homophilic adhesion as well as heterophilic adhesion with CD6, NgCAM and high-density lipoprotein. Poor axonal fasciculation is observed in retinal ganglion cell axons within retinal and motor axons within intercostal nerves of BEN-deficient mice, resulting in severe retinal dysplasia, including retinal folds and photoreceptor ectopias (Weiner et al., 2004).
DsCAM has ten Ig-like domains and six fibronectin type III repeats and mediates homophilic adhesion. DsCAM plays an early and essential role in promoting selective fasciculation of young axons in the peduncle of mushroom body neurons in Drosophila (Zhan et al., 2004).
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Outlook |
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Acknowledgments |
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References |
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