Glycosylphosphatidylinositol- Anchored Immunoglobulin Superfamily Cell Adhesion Molecules and Their Role in Neuronal Development and Synapse Regulation
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fnmol-10-00378 November 13, 2017 Time: 16:57 # 1 REVIEW published: 15 November 2017 doi: 10.3389/fnmol.2017.00378 Glycosylphosphatidylinositol- Anchored Immunoglobulin Superfamily Cell Adhesion Molecules and Their Role in Neuronal Development and Synapse Regulation Rui P. A. Tan, Iryna Leshchyns’ka and Vladimir Sytnyk* School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia Immunoglobulin superfamily (IgSF) cell adhesion molecules (CAMs) are cell surface glycoproteins that not only mediate interactions between neurons but also between neurons and other cells in the nervous system. While typical IgSF CAMs are transmembrane molecules, this superfamily also includes CAMs, which do not possess transmembrane and intracellular domains and are instead attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. In this review, we focus Edited by: on the role GPI-anchored IgSF CAMs have as signal transducers and ligands in Jaewon Ko, Daegu Gyeongbuk Institute of neurons, and discuss their functions in regulation of neuronal development, synapse Science and Technology (DGIST), formation, synaptic plasticity, learning, and behavior. We also review the links between South Korea GPI-anchored IgSF CAMs and brain disorders. Reviewed by: Davide Comoletti, Keywords: cell adhesion molecules, neuronal, GPI anchor, synapses, neurite outgrowth, synaptic plasticity Rutgers University, The State (LTP/LTD), learning and memory University of New Jersey, United States Valentin Stein, INTRODUCTION University of Bonn, Germany *Correspondence: Cell adhesion molecules (CAMs) are expressed across all cell types. In the nervous system, multiple Vladimir Sytnyk families of CAMs are expressed in neurons, including integrins, cadherins, selectins, neuroligins, [email protected] neurexins, and the immunoglobulin superfamily (IgSF) of CAMs (Brümmendorf and Rathjen, 1993; Chothia and Jones, 1997; Buckley et al., 1998; Südhof, 2008; Sytnyk et al., 2017). These Received: 14 September 2017 Accepted: 30 October 2017 molecules play numerous roles in the developing and mature nervous system by regulating growth Published: 15 November 2017 and branching of neurites, navigating growing axons and dendrites to the appropriate targets, regulating formation and maturation of synaptic contacts, and maintaining synapse function and Citation: Tan RPA, Leshchyns’ka I and plasticity during learning and memory formation. Sytnyk V (2017) Typically, and for some families exclusively, CAMs are transmembrane proteins. While the Glycosylphosphatidylinositol- extracellular domains of these molecules mediate interactions not only between neurons but Anchored Immunoglobulin also between neurons and other cells by interacting with the same molecules or other types of Superfamily Cell Adhesion Molecules molecules either on the membranes of other cells or in the extracellular matrix, the intracellular and Their Role in Neuronal domains are involved in interactions with the cytoskeleton and signal transduction (Leshchyns’ka Development and Synapse Regulation. and Sytnyk, 2016). However, CAMs can also be anchored to the plasma membranes via a Front. Mol. Neurosci. 10:378. glycosylphosphatidylinositol (GPI) anchor, with the highest number of the GPI-anchored CAMs doi: 10.3389/fnmol.2017.00378 within the IgSF (Figure 1 and Table 1). Although these proteins do not possess intracellular Frontiers in Molecular Neuroscience| www.frontiersin.org 1 November 2017| Volume 10| Article 378 fnmol-10-00378 November 13, 2017 Time: 16:57 # 2 Tan et al. GPI-Anchored IgSF CAMs in Neurons domains, their functions are not limited to mediating cell Ectodomains of IgSF CAMs may also contain fibronectin adhesion only. In this review, we summarize the role GPI- type III repeats, which are also present in ectodomains of anchored IgSF CAMs have as signal transducers, ligands, synapse some GPI-anchored IgSF CAMs, such as contactin-1, -2, -3 formation regulators, as well as their role in synaptic plasticity (Figures 1, 2). and brain disorders. In the human and murine genomes, genes coding for GPI-anchored IgSF CAMs include NEGR1, opioid-binding cell GPI-Anchored IgSF CAMs and Their adhesion molecule (OBCAM), neurotrimin (Ntm), limbic system- Homophilic and Heterophilic Interactions associated membrane protein (LAMP), IgLON5, contactin-1, -2, Immunoglobulin superfamily CAMs are identified by the -3, -4, -5, -6, Thy-1, and carcinoembryonic antigen-related cell presence of immunoglobulin (Ig)-like domains in their adhesion molecule (CEACAM)-5, -6, -7, and -8 (Williams and ectodomains. There are several types of Ig domains present Gagnon, 1982; Oikawa et al., 1987; Yoshihara et al., 1994, 1995; in IgSF CAMs including C2-, V-, and I-type (Williams and Hachisuka et al., 1996; Ogawa et al., 1996; Funatsu et al., 1999; Barclay, 1988; Harpaz and Chothia, 1994). The V-type is Itoh et al., 2008; Sabater et al., 2016)(Table 1 and Figure 1). similar to the variable V-domain in Igs, whereas the C2 type OBCAM, Ntm, LAMP, NEGR1, and IgLON5 constitute the is similar to C1-domains in Igs (Barclay, 2003). The I-type IgLON family (Yamada et al., 2007; Hashimoto et al., 2009; Sanz (I for intermediate) shares similarities with C1- and V-type et al., 2015). In addition, short isoforms of some transmembrane domains and was initially identified in Telokin, an intracellular IgSF CAMs, such as the shortest isoform of the neural cell smooth muscle protein (Harpaz and Chothia, 1994). GPI- adhesion molecule (NCAM) with the molecular weight 120 kDa anchored IgSF CAMs differ in the numbers of V-, C2-, or (NCAM120), are also GPI-anchored (Hemperly et al., 1986). I-type Ig domains present in their ectodomains. For example, Glycosylphosphatidylinositol-anchoring of proteins to the only one V-type Ig domain is present in Thy-1, while there plasma membranes is a highly conserved post-translational are three C2-type Ig domains present in neuronal growth modification across all eukaryotes (Fujita and Kinoshita, 2012). regulator 1 (NEGR1), and six C2-type domains present in The GPI anchor is a complex structure consisting of a contactin-1, -2, -3 (Ranscht, 1988; Williams and Barclay, 1988; phosphoethanolamine linker, glycan core, and phospholipid Brümmendorf et al., 1989; Zuellig et al., 1992; Figure 1). The tail. Structural variations of the anchor are possible by the first four Ig domains of contactin-2 have also been classified as modification of phosphoinositol, glucosamine, and mannose I-type Ig domains in some studies (Harpaz and Chothia, 1994; residues within the glycan core (Paulick and Bertozzi, 2008; Freigang et al., 2000). All Ig domains of the IgSF CAMs have Fujita and Kinoshita, 2012). Application of phosphatidylinositol- a core of two b-sheets facing each other and stabilized by an specific phospholipase C (PI-PLC), an enzyme capable of cleaving intra-chain disulfide bridge (Chothia et al., 1998; Figure 2). the GPI anchor, induces removal of GPI-anchored IgSF CAMs FIGURE 1 | Examples of the GPI-anchored IgSF CAMs. Structural domains and putative glycosylation sites in the GPI-anchored IgSF CAMs are represented according to the Uniprot database. SS, disulfide bridges present in Ig domains. Frontiers in Molecular Neuroscience| www.frontiersin.org 2 November 2017| Volume 10| Article 378 fnmol-10-00378 November 13, 2017 Time: 16:57 # 3 Tan et al. GPI-Anchored IgSF CAMs in Neurons from the cell surface, indicating that the GPI anchor is critical GPI-Anchored IgSF CAMs As Functional for the attachment of these proteins to the cellular membranes Receptors (Sanz et al., 2015). The complexity of the GPI anchor, however, The role for IgSF CAMs as functional receptors has been suggests that it also plays a role in other multiple functions suggested by studies analyzing effects of antibodies against these aside from membrane anchorage, including signal transduction, molecules on neurite outgrowth. Early studies using antibodies protein sorting, as well as the structure and function regulation of against Thy-1 as a growth substrate showed that Thy-1 antibodies the GPI-anchored IgSF CAMs. In particular, the GPI anchor links enhance regeneration of neurites in rat retinal ganglion neurons these molecules to membrane microdomains that are insoluble and promote survival of mouse cerebellar Purkinje cells (Leifer in cold non-ionic detergents (Varma and Mayor, 1998; Fujita et al., 1984; Messer et al., 1984). Similarly, antibodies against and Kinoshita, 2012). Such specialized membrane microdomains Thy-1 promote neurite outgrowth in rat dorsal root ganglion are referred to as lipid rafts and render GPI-anchored proteins (DRG) neurons when applied in the culture medium (Chen et al., resistant to cold non-ionic detergent extraction (Schroeder et al., 2005). Later, natural ligands of GPI-anchored IgSF CAMs have 1994; Simons and Ikonen, 1997). also been shown to induce neurite outgrowth changes. Retinal The ectodomains of GPI-anchored IgSF CAMs contain ganglion cells from Thy-1 knock-out mice show impaired neurite multiple glycosylation sites. For example, IgLON protein outgrowth over different substrates made of the proteins of family members with three Ig domains contain six or seven the extracellular matrix, including fibronectin and collagen, and N-glycosylation sites in their ectodomains (Figure 1; Pimenta Thy-1 knock-out mice demonstrate abnormal retinal formation et al., 1996; Itoh et al., 2008). NCAM120 is a prominent with thinner retinae (Simon et al., 1999). Thy-1 has also been example of a