Expression and known function of junctional molecules at brain barriers
| Junctional molecule | General characteristics | Brain barrier expression/localization | Function in cell-to-cell contacts |
| Transmembrane AJ proteins | |||
| E-cadherin (uvomorulin, L-CAM) | Main integral membrane protein of epithelial AJs; member of classical cadherin family (Type I) mediating homophilic adhesions in cis and trans; links to actin cytoskeleton via catenin complex (Vestweber, 2015) | Basolateral localization in rat and chicken choroid plexus epithelium (Marrs et al., 1993) and epithelial cells of benign human choroid plexus tumors (Figarella-Branger et al., 1995) | Core homophilic cell adhesion molecule of epithelial AJs, controls epithelial cell contact formation, barrier integrity, junctional plasticity, and cytoskeletal tension |
| VE-cadherin (cadherin-5) | Main integral membrane protein of endothelial AJs; member of the classical cadherin family (Type II) mediating homophilic adhesions in cis and trans; cytoplasmic domain links AJs via catenin complex to actin cytoskeleton and intermediate filaments (for review see Dejana and Vestweber, 2013) | At junctions in mouse CNS blood vessels even during embryonic development (Breier et al., 1996); localizes to junctions in rat and human brain microvessels (Vorbrodt and Dobrogowska, 2003) | Core homophilic cell adhesion molecule of endothelial AJs; controls endothelial cell survival, stabilization of blood vessel assembly, and vascular permeability (Carmeliet et al., 1999; Crosby et al., 2005) |
| N-cadherin (cadherin-2) | Transmembrane protein of the classical cadherin family (Type I) | Protein detected during early angiogenesis at the abluminal surface of eye and brain endothelial cells (Gerhardt et al., 1999) | Mediates pericyte–endothelial interactions during brain angiogenesis (Gerhardt et al., 2000) |
| VE-PTP | Endothelial-specific phospho tyrosine phosphatase (VE-PTP) | VE-PTP-LacZ reporter expression observed in brain vessels during embryonic development (Bäumer et al., 2006) | Controls VE-cadherin phosphorylation and thus vascular junctional integrity and leukocyte diapedesis (Küppers et al., 2014) |
| Nectin | Member of the nectin family of the Ig superfamily; mediates homophilic or heterophilic interactions with other nectins (Indra et al., 2013); highly conserved cytoplasmic tail binds to the adaptor protein afadin (AF-6), linking nectins to actin cytoskeleton | Afadin observed in choroid plexus epithelium, suggesting presence of nectin (Lagaraine et al., 2011) | Nectin–afadin complex involved in the formation of AJs (Ikeda et al., 1999) and TJs (Takai et al., 2003) |
| Transmembrane TJ proteins | |||
| Occludin | Integral membrane protein localized exclusively to TJs (Furuse et al., 1993); Type II transmembrane protein with a tetraspanning Marvel (MAL and related proteins for vesicle trafficking and membrane link) motif; member of the TAMP family (like Tricellulin and MarvelD3) sharing the Marvel domain (Raleigh et al., 2010) | High expression and strong junctional localization in chicken brain microvessels (Furuse et al., 1993; Hirase et al., 1997) and in mouse BCSFB epithelial cells (Wolburg et al., 2001; Diez-Roux et al., 2011; Kratzer et al., 2012) | Links TJs to the actin cytoskeleton by recruiting scaffolding proteins of the MAGUK (membrane associated with a guanylyl kinase-like domain) family, such as zonula occludens 1 (ZO-1), ZO-2, and ZO-3 (Morita et al., 1999; Nasdala et al., 2002); regulates Ca2+ transport across BBB (Saitou et al., 2000); localizes tricellulin to tricellular TJs (Ikenouchi et al., 2008); regulates paracellular permeability via its phosphorylation status (Raleigh et al., 2011) |
| Tricellulin | TAMP family member (like occludin; Raleigh et al., 2010) | Restricted localization to tricellular TJs of BBB, recruited by the angulin/LSR-family (Furuse et al., 2014); absent in fenestrated endothelial cells of choroid plexus (Iwamoto et al., 2014) | Required for full barrier formation of in vitro cultured epithelial cells (Iwamoto et al., 2014) |
| Claudin-1 | Member of the claudin family of tetraspanning TJ-specific membrane proteins (Furuse et al., 1998); form the backbone of TJs by establishing homophilic and heterophilic interactions in cis and trans via their extracellular loops (Piontek et al., 2008); essential and sufficient to induce TJs in fibroblasts (Furuse et al., 1998); PDZ-binding motif at the claudin carboxy terminus mediates interaction with the scaffolding proteins ZO-1, ZO-2, and ZO-3, which contributes to TJ strand organization (for review see Van Itallie and Anderson, 2014) | mRNA detected in mouse BCSFB (Kratzer et al., 2012) and protein localized to mouse BCSFB junctions (Wolburg et al., 2001); discrepant observations of expression in BBB: there is an absence of mRNA and protein in mouse brain parenchymal brain microvessels but a presence of protein in meningeal brain microvessels (Pfeiffer et al., 2011); protein detected in brain endothelial TJs (Haseloff et al., 2015) | Induces and seals TJs; regulates paracellular movement of water (skin) and macromolecules (Furuse et al., 2002); claudin-1 overexpression in brain endothelial cells of mouse models of neuroinflammation reduces BBB leakiness and ameliorates clinical disease (Pfeiffer et al., 2011). |
| Claudin-2 | See general comments on claudin family above for claudin-1 | mRNA and protein localizes to BCSFB (Wolburg et al., 2001; Kratzer et al., 2012) | This pore forming claudin (Furuse et al., 2001) regulates paracellular ion and water flow; claudin-2–deficient mice are viable, BCSFB function has not yet been analyzed (Muto et al., 2010) |
| Claudin-3 | See general comments on claudin family above for claudin-1 | Detected in TJs in brain endothelial cells in some studies (Wolburg et al., 2003) but not in others (Ohtsuki et al., 2008; Daneman et al., 2010a); induced during brain angiogenesis by canonical Wnt/β-catenin signaling (Liebner et al., 2008); expressed in choroid plexus epithelial cells and localizes to TJs (Wolburg et al., 2003; Kratzer et al., 2012; Kooij et al., 2014) | Expression is induced during brain angiogenesis and correlates with barriergenesis (Liebner et al., 2008); sealing of BCSFB but not BBB TJs under neuroinflammatory conditions as detected in claudin-3–deficient mice (Kooij et al., 2014) |
| Claudin-5 | Endothelial cell–specific component of TJ strands (Morita et al., 1999) | Highly expressed in BBB TJs in zebrafish, rodents, nonhuman primates, and humans (Nitta et al., 2003; Jeong et al., 2008; Hoshi et al., 2013); junctional localization in zebrafish BCSFB (Henson et al., 2014) | Claudin-5–deficient mice do not survive due to BBB leakiness to molecules <800 D (Nitta et al., 2003); focal loss of claudin-5 correlates with BBB dysfunction (Zhou et al., 2014) |
| Claudin-11 | Induces parallel-array TJ strands in myelin sheaths of oligodendrocytes (Gow et al., 1999); claudin-11–deficient mice develop neurological deficits including deafness (Gow et al., 1999, 2004) | Localizes to TJs of BCSFB in mice (Wolburg et al., 2001) | TJs of the BCSFB are characterized by parallel running particle strands (Wolburg and Paulus, 2010) probably induced by claudin-11 |
| Claudin-12 | See general comments on the claudin family above for claudin-1; claudin-12 lacks a C-terminal PDZ-binding motif | Shown to be specifically expressed in and to localize to TJs of brain endothelial cells by some laboratories (Nitta et al., 2003; Schrade et al., 2012) but not by others (Ohtsuki et al., 2008; Daneman et al., 2010a) | Function at BBB unknown |
| Additional claudins | See general comments on claudin family above | mRNA and protein of additional claudins detected in mouse choroid plexus (Kratzer et al., 2012); mRNA of additional claudins detected in purified brain microvessels (Hoshi et al., 2013); additional claudin proteins detected in rat and marmoset brain microvessels (Ohtsuki et al., 2008) | Functions in brain barriers unknown |
| JAM-A (Junctional adhesion molecule A, JAM-1) | Type I transmembrane protein and member of the classical JAM family of the Ig superfamily; two extracellular Ig-like domains, cytoplasmic tail with a PDZ-binding motif; JAMs engage in homophilic and heterophilic interactions among their family members and bind integrins (Martìn-Padura et al., 1998; for review see Garrido-Urbani et al., 2014) | Expressed in and localized to mouse and human BBB endothelial TJs (Aurrand-Lions et al., 2001b; Vorbrodt and Dobrogowska, 2004; Padden et al., 2007) | Regulates cell polarity by intracellular association with the PAR-3/atypical protein kinase C (aPKC)/PAR-6 complex (Ebnet et al., 2001) and leukocyte trafficking across endothelial barriers including the BBB (Martìn-Padura et al., 1998; Williams et al., 2013); loss of vascular JAM-A immunostaining in human brain tissue correlates with BBB leakiness (Padden et al., 2007) |
| JAM-B (human JAM-2; human and mouse VE-JAM; mouse JAM-3) | See explanation for JAM-A | Expressed in and localized to TJs at mouse BBB (Aurrand-Lions et al., 2001a,b) | Leukocyte trafficking across skin endothelium (Ludwig et al., 2009); function at brain barriers is unknown |
| JAM-C (human JAM-3; mouse JAM-2) | See explanation for JAM-A | Localizes to TJs in mouse BBB and BCSFB (Arrate et al., 2001; Wyss et al., 2012) | Might contribute to human BBB integrity (Mochida et al., 2010); JAM-C−/− C57BL/6 mice develop a hydrocephalus independent of endothelial JAM-C, suggesting that JAM-C at the BCSFB might influence brain fluid homeostasis (Wyss et al., 2012) |
| Transmembrane proteins outside of organized AJs and TJs | |||
| PECAM-1 | Type I integral membrane protein of the Ig superfamily with six extracellular Ig domains, a short transmembrane, and a long cytoplasmic domain that can be serine and tyrosine phosphorylated upon cellular activation; highly expressed in all endothelial cells (summarized in Privratsky and Newman, 2014) | Highly expressed in endothelial cell-to-cell junctions outside of organized AJs and TJs, including the BBB (Graesser et al., 2002; Lyck et al., 2009) | Contributes to steady-state barrier function of endothelial cells; functions as a mechanosensor and accelerates restoration of barrier integrity following perturbations, including the BBB (Graesser et al., 2002; Privratsky and Newman, 2014) |
| CD99 and CD99L | Heavily O-glycosylated type I transmembrane proteins (Schenkel et al., 2002) | Localizes to endothelial cell-to-cell contacts including those of brain endothelial cells (Bixel et al., 2004). | Immune cell trafficking across brain endothelium in vitro (Bixel et al., 2004) |
| Intracellular scaffolding proteins of AJs | |||
| p120-catenin | Armadillo-repeat protein (Harris, 2012); binds to the juxtamembrane region of the cytoplasmic domain of both VE- and E-cadherin | Detected at ultrastructural level in AJs in human brain microvessels (Vorbrodt and Dobrogowska, 2004) | Stabilizes AJs by inhibiting constitutive endocytosis of cadherins; regulates activity of Rho family GTPases and thus actin cytoskeleton dynamics; recruits microtubules to the cadherin complex (Vestweber, 2015) |
| β-Catenin | Armadillo repeat protein (Harris, 2012); binds to the distal region of the cytoplasmic domain of VE- and E-cadherin and mediates interaction with α-catenin that engages F-actin, thus linking the AJ complex with the actin cytoskeleton (Buckley et al., 2014) | Localizes to AJs of BBB in chicken and mouse (Liebner et al., 2000a) and to AJs of BCSFB in rats (Lippoldt et al., 2000); early association with endothelial N-cadherin during brain angiogenesis followed by junctional localization (Liebner et al., 2000a); localizes to endothelial nuclei during brain angiogenesis to regulate transcription (summarized in Engelhardt and Liebner, 2014) | Stabilizes AJs by inhibiting proteolysis of cadherins (Vestweber, 2015); regulates BBB differentiation during brain angiogenesis by inducing expression of claudin-3 via the canonical Wnt/β-catenin signaling pathway (summarized in Engelhardt and Liebner, 2014) |
| γ-Catenin (plakoglobin) | Binds to the cytoplasmic tail of VE-cadherin | Shown to localize to AJ of BBB in chickens (Liebner et al., 2000a) | Links cadherin complex to intermediate filaments |
| α-Catenin | α-Catenin binds directly or indirectly to β-catenin and to the actin cytoskeleton | Localizes at the ultrastructural level to interendothelial junctions of vessels in human or mouse brain tissue sections (Vorbrodt and Dobrogowska, 2003); localizes to AJs at rat BCSFB (Lippoldt et al., 2000) | Anchors AJs to the actin cytoskeleton; regulates the adhesive function of cadherins (summarized in Vestweber, 2015) |
| Intracellular scaffolding protein TJs | |||
| ZO-1 (Zonnula occludens -1) | TJ scaffolding protein of the MAGUK (membrane associated with a guanylyl kinase-like domain) family; binds to integral TJ proteins, ZO-2, and F-actin (for review see Van Itallie and Anderson, 2014). | Localizes to BBB junctions in mouse (Nico et al., 1999) and human brain tissue (Kirk et al., 2003; Vorbrodt and Dobrogowska, 2003); localizes to TJs in mouse BCSFB (Wolburg et al., 2001; Kratzer et al., 2012); also localizes to AJs by binding to α-catenin and F-actin (Itoh et al., 1999) | ZO-1 organizes components of TJs in epithelial cells as well as both TJs and AJs in endothelial cells, and links them to the cortical actin cytoskeleton (Fanning et al., 1998; Itoh et al., 1999); central regulator of VE-cadherin–dependent AJs (Tornavaca et al., 2015) |
| ZO-2 | TJ scaffolding protein of the MAGUK family | Associates with junctions in primary bovine and human brain microvascular endothelial cells in vitro (Mark and Davis, 2002; Lee et al., 2009); ZO-2 mRNA detected in choroid plexus of mice (Kratzer et al., 2012) | Can replace ZO-1 in TJs |
| ZO-3 | TJ scaffolding protein of the MAGUK family | Low mRNA expression levels in mouse choroid plexus and brain microvascular endothelial cells (Kratzer et al., 2012) and mRNA and protein detected in choroid plexus of ewes (Lagaraine et al., 2011) | Can replace ZO-1 and ZO-2 in TJs |
| Junctional molecule | General characteristics | Brain barrier expression/localization | Function in cell-to-cell contacts |
| Transmembrane AJ proteins | |||
| E-cadherin (uvomorulin, L-CAM) | Main integral membrane protein of epithelial AJs; member of classical cadherin family (Type I) mediating homophilic adhesions in cis and trans; links to actin cytoskeleton via catenin complex (Vestweber, 2015) | Basolateral localization in rat and chicken choroid plexus epithelium (Marrs et al., 1993) and epithelial cells of benign human choroid plexus tumors (Figarella-Branger et al., 1995) | Core homophilic cell adhesion molecule of epithelial AJs, controls epithelial cell contact formation, barrier integrity, junctional plasticity, and cytoskeletal tension |
| VE-cadherin (cadherin-5) | Main integral membrane protein of endothelial AJs; member of the classical cadherin family (Type II) mediating homophilic adhesions in cis and trans; cytoplasmic domain links AJs via catenin complex to actin cytoskeleton and intermediate filaments (for review see Dejana and Vestweber, 2013) | At junctions in mouse CNS blood vessels even during embryonic development (Breier et al., 1996); localizes to junctions in rat and human brain microvessels (Vorbrodt and Dobrogowska, 2003) | Core homophilic cell adhesion molecule of endothelial AJs; controls endothelial cell survival, stabilization of blood vessel assembly, and vascular permeability (Carmeliet et al., 1999; Crosby et al., 2005) |
| N-cadherin (cadherin-2) | Transmembrane protein of the classical cadherin family (Type I) | Protein detected during early angiogenesis at the abluminal surface of eye and brain endothelial cells (Gerhardt et al., 1999) | Mediates pericyte–endothelial interactions during brain angiogenesis (Gerhardt et al., 2000) |
| VE-PTP | Endothelial-specific phospho tyrosine phosphatase (VE-PTP) | VE-PTP-LacZ reporter expression observed in brain vessels during embryonic development (Bäumer et al., 2006) | Controls VE-cadherin phosphorylation and thus vascular junctional integrity and leukocyte diapedesis (Küppers et al., 2014) |
| Nectin | Member of the nectin family of the Ig superfamily; mediates homophilic or heterophilic interactions with other nectins (Indra et al., 2013); highly conserved cytoplasmic tail binds to the adaptor protein afadin (AF-6), linking nectins to actin cytoskeleton | Afadin observed in choroid plexus epithelium, suggesting presence of nectin (Lagaraine et al., 2011) | Nectin–afadin complex involved in the formation of AJs (Ikeda et al., 1999) and TJs (Takai et al., 2003) |
| Transmembrane TJ proteins | |||
| Occludin | Integral membrane protein localized exclusively to TJs (Furuse et al., 1993); Type II transmembrane protein with a tetraspanning Marvel (MAL and related proteins for vesicle trafficking and membrane link) motif; member of the TAMP family (like Tricellulin and MarvelD3) sharing the Marvel domain (Raleigh et al., 2010) | High expression and strong junctional localization in chicken brain microvessels (Furuse et al., 1993; Hirase et al., 1997) and in mouse BCSFB epithelial cells (Wolburg et al., 2001; Diez-Roux et al., 2011; Kratzer et al., 2012) | Links TJs to the actin cytoskeleton by recruiting scaffolding proteins of the MAGUK (membrane associated with a guanylyl kinase-like domain) family, such as zonula occludens 1 (ZO-1), ZO-2, and ZO-3 (Morita et al., 1999; Nasdala et al., 2002); regulates Ca2+ transport across BBB (Saitou et al., 2000); localizes tricellulin to tricellular TJs (Ikenouchi et al., 2008); regulates paracellular permeability via its phosphorylation status (Raleigh et al., 2011) |
| Tricellulin | TAMP family member (like occludin; Raleigh et al., 2010) | Restricted localization to tricellular TJs of BBB, recruited by the angulin/LSR-family (Furuse et al., 2014); absent in fenestrated endothelial cells of choroid plexus (Iwamoto et al., 2014) | Required for full barrier formation of in vitro cultured epithelial cells (Iwamoto et al., 2014) |
| Claudin-1 | Member of the claudin family of tetraspanning TJ-specific membrane proteins (Furuse et al., 1998); form the backbone of TJs by establishing homophilic and heterophilic interactions in cis and trans via their extracellular loops (Piontek et al., 2008); essential and sufficient to induce TJs in fibroblasts (Furuse et al., 1998); PDZ-binding motif at the claudin carboxy terminus mediates interaction with the scaffolding proteins ZO-1, ZO-2, and ZO-3, which contributes to TJ strand organization (for review see Van Itallie and Anderson, 2014) | mRNA detected in mouse BCSFB (Kratzer et al., 2012) and protein localized to mouse BCSFB junctions (Wolburg et al., 2001); discrepant observations of expression in BBB: there is an absence of mRNA and protein in mouse brain parenchymal brain microvessels but a presence of protein in meningeal brain microvessels (Pfeiffer et al., 2011); protein detected in brain endothelial TJs (Haseloff et al., 2015) | Induces and seals TJs; regulates paracellular movement of water (skin) and macromolecules (Furuse et al., 2002); claudin-1 overexpression in brain endothelial cells of mouse models of neuroinflammation reduces BBB leakiness and ameliorates clinical disease (Pfeiffer et al., 2011). |
| Claudin-2 | See general comments on claudin family above for claudin-1 | mRNA and protein localizes to BCSFB (Wolburg et al., 2001; Kratzer et al., 2012) | This pore forming claudin (Furuse et al., 2001) regulates paracellular ion and water flow; claudin-2–deficient mice are viable, BCSFB function has not yet been analyzed (Muto et al., 2010) |
| Claudin-3 | See general comments on claudin family above for claudin-1 | Detected in TJs in brain endothelial cells in some studies (Wolburg et al., 2003) but not in others (Ohtsuki et al., 2008; Daneman et al., 2010a); induced during brain angiogenesis by canonical Wnt/β-catenin signaling (Liebner et al., 2008); expressed in choroid plexus epithelial cells and localizes to TJs (Wolburg et al., 2003; Kratzer et al., 2012; Kooij et al., 2014) | Expression is induced during brain angiogenesis and correlates with barriergenesis (Liebner et al., 2008); sealing of BCSFB but not BBB TJs under neuroinflammatory conditions as detected in claudin-3–deficient mice (Kooij et al., 2014) |
| Claudin-5 | Endothelial cell–specific component of TJ strands (Morita et al., 1999) | Highly expressed in BBB TJs in zebrafish, rodents, nonhuman primates, and humans (Nitta et al., 2003; Jeong et al., 2008; Hoshi et al., 2013); junctional localization in zebrafish BCSFB (Henson et al., 2014) | Claudin-5–deficient mice do not survive due to BBB leakiness to molecules <800 D (Nitta et al., 2003); focal loss of claudin-5 correlates with BBB dysfunction (Zhou et al., 2014) |
| Claudin-11 | Induces parallel-array TJ strands in myelin sheaths of oligodendrocytes (Gow et al., 1999); claudin-11–deficient mice develop neurological deficits including deafness (Gow et al., 1999, 2004) | Localizes to TJs of BCSFB in mice (Wolburg et al., 2001) | TJs of the BCSFB are characterized by parallel running particle strands (Wolburg and Paulus, 2010) probably induced by claudin-11 |
| Claudin-12 | See general comments on the claudin family above for claudin-1; claudin-12 lacks a C-terminal PDZ-binding motif | Shown to be specifically expressed in and to localize to TJs of brain endothelial cells by some laboratories (Nitta et al., 2003; Schrade et al., 2012) but not by others (Ohtsuki et al., 2008; Daneman et al., 2010a) | Function at BBB unknown |
| Additional claudins | See general comments on claudin family above | mRNA and protein of additional claudins detected in mouse choroid plexus (Kratzer et al., 2012); mRNA of additional claudins detected in purified brain microvessels (Hoshi et al., 2013); additional claudin proteins detected in rat and marmoset brain microvessels (Ohtsuki et al., 2008) | Functions in brain barriers unknown |
| JAM-A (Junctional adhesion molecule A, JAM-1) | Type I transmembrane protein and member of the classical JAM family of the Ig superfamily; two extracellular Ig-like domains, cytoplasmic tail with a PDZ-binding motif; JAMs engage in homophilic and heterophilic interactions among their family members and bind integrins (Martìn-Padura et al., 1998; for review see Garrido-Urbani et al., 2014) | Expressed in and localized to mouse and human BBB endothelial TJs (Aurrand-Lions et al., 2001b; Vorbrodt and Dobrogowska, 2004; Padden et al., 2007) | Regulates cell polarity by intracellular association with the PAR-3/atypical protein kinase C (aPKC)/PAR-6 complex (Ebnet et al., 2001) and leukocyte trafficking across endothelial barriers including the BBB (Martìn-Padura et al., 1998; Williams et al., 2013); loss of vascular JAM-A immunostaining in human brain tissue correlates with BBB leakiness (Padden et al., 2007) |
| JAM-B (human JAM-2; human and mouse VE-JAM; mouse JAM-3) | See explanation for JAM-A | Expressed in and localized to TJs at mouse BBB (Aurrand-Lions et al., 2001a,b) | Leukocyte trafficking across skin endothelium (Ludwig et al., 2009); function at brain barriers is unknown |
| JAM-C (human JAM-3; mouse JAM-2) | See explanation for JAM-A | Localizes to TJs in mouse BBB and BCSFB (Arrate et al., 2001; Wyss et al., 2012) | Might contribute to human BBB integrity (Mochida et al., 2010); JAM-C−/− C57BL/6 mice develop a hydrocephalus independent of endothelial JAM-C, suggesting that JAM-C at the BCSFB might influence brain fluid homeostasis (Wyss et al., 2012) |
| Transmembrane proteins outside of organized AJs and TJs | |||
| PECAM-1 | Type I integral membrane protein of the Ig superfamily with six extracellular Ig domains, a short transmembrane, and a long cytoplasmic domain that can be serine and tyrosine phosphorylated upon cellular activation; highly expressed in all endothelial cells (summarized in Privratsky and Newman, 2014) | Highly expressed in endothelial cell-to-cell junctions outside of organized AJs and TJs, including the BBB (Graesser et al., 2002; Lyck et al., 2009) | Contributes to steady-state barrier function of endothelial cells; functions as a mechanosensor and accelerates restoration of barrier integrity following perturbations, including the BBB (Graesser et al., 2002; Privratsky and Newman, 2014) |
| CD99 and CD99L | Heavily O-glycosylated type I transmembrane proteins (Schenkel et al., 2002) | Localizes to endothelial cell-to-cell contacts including those of brain endothelial cells (Bixel et al., 2004). | Immune cell trafficking across brain endothelium in vitro (Bixel et al., 2004) |
| Intracellular scaffolding proteins of AJs | |||
| p120-catenin | Armadillo-repeat protein (Harris, 2012); binds to the juxtamembrane region of the cytoplasmic domain of both VE- and E-cadherin | Detected at ultrastructural level in AJs in human brain microvessels (Vorbrodt and Dobrogowska, 2004) | Stabilizes AJs by inhibiting constitutive endocytosis of cadherins; regulates activity of Rho family GTPases and thus actin cytoskeleton dynamics; recruits microtubules to the cadherin complex (Vestweber, 2015) |
| β-Catenin | Armadillo repeat protein (Harris, 2012); binds to the distal region of the cytoplasmic domain of VE- and E-cadherin and mediates interaction with α-catenin that engages F-actin, thus linking the AJ complex with the actin cytoskeleton (Buckley et al., 2014) | Localizes to AJs of BBB in chicken and mouse (Liebner et al., 2000a) and to AJs of BCSFB in rats (Lippoldt et al., 2000); early association with endothelial N-cadherin during brain angiogenesis followed by junctional localization (Liebner et al., 2000a); localizes to endothelial nuclei during brain angiogenesis to regulate transcription (summarized in Engelhardt and Liebner, 2014) | Stabilizes AJs by inhibiting proteolysis of cadherins (Vestweber, 2015); regulates BBB differentiation during brain angiogenesis by inducing expression of claudin-3 via the canonical Wnt/β-catenin signaling pathway (summarized in Engelhardt and Liebner, 2014) |
| γ-Catenin (plakoglobin) | Binds to the cytoplasmic tail of VE-cadherin | Shown to localize to AJ of BBB in chickens (Liebner et al., 2000a) | Links cadherin complex to intermediate filaments |
| α-Catenin | α-Catenin binds directly or indirectly to β-catenin and to the actin cytoskeleton | Localizes at the ultrastructural level to interendothelial junctions of vessels in human or mouse brain tissue sections (Vorbrodt and Dobrogowska, 2003); localizes to AJs at rat BCSFB (Lippoldt et al., 2000) | Anchors AJs to the actin cytoskeleton; regulates the adhesive function of cadherins (summarized in Vestweber, 2015) |
| Intracellular scaffolding protein TJs | |||
| ZO-1 (Zonnula occludens -1) | TJ scaffolding protein of the MAGUK (membrane associated with a guanylyl kinase-like domain) family; binds to integral TJ proteins, ZO-2, and F-actin (for review see Van Itallie and Anderson, 2014). | Localizes to BBB junctions in mouse (Nico et al., 1999) and human brain tissue (Kirk et al., 2003; Vorbrodt and Dobrogowska, 2003); localizes to TJs in mouse BCSFB (Wolburg et al., 2001; Kratzer et al., 2012); also localizes to AJs by binding to α-catenin and F-actin (Itoh et al., 1999) | ZO-1 organizes components of TJs in epithelial cells as well as both TJs and AJs in endothelial cells, and links them to the cortical actin cytoskeleton (Fanning et al., 1998; Itoh et al., 1999); central regulator of VE-cadherin–dependent AJs (Tornavaca et al., 2015) |
| ZO-2 | TJ scaffolding protein of the MAGUK family | Associates with junctions in primary bovine and human brain microvascular endothelial cells in vitro (Mark and Davis, 2002; Lee et al., 2009); ZO-2 mRNA detected in choroid plexus of mice (Kratzer et al., 2012) | Can replace ZO-1 in TJs |
| ZO-3 | TJ scaffolding protein of the MAGUK family | Low mRNA expression levels in mouse choroid plexus and brain microvascular endothelial cells (Kratzer et al., 2012) and mRNA and protein detected in choroid plexus of ewes (Lagaraine et al., 2011) | Can replace ZO-1 and ZO-2 in TJs |