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Correspondence to Britta Engelhardt: [email protected] Abbreviations used in this paper: AJ, adherens junction; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal fluid barrier; CCM, cerebral cavernous malformation; CNS, central nervous system; E-cadherin, epithelial cadherin; EAE, experimental autoimmune encephalomyelitis; Ig, immunoglobulin; MS, multiple sclerosis; RA, retinoic acid; Shh, Sonic hedgehog; TJ, tight junction; VE-cadherin, vascular endothelial cadherin. Introduction The endothelial blood–brain barrier (BBB), composed of the highly specialized central nervous system (CNS) microvascular endothelial cells, and the epithelial blood–cerebrospinal fluid barrier (BCSFB), composed of the choroid plexus epithelial cells, protect the CNS from the constantly changing milieu in the bloodstream as well as infections and toxins, and are thus essential for maintaining CNS homeostasis (Fig. 1). Work on how these barriers prevent paracellular diffusion of harmful elements into the CNS usually focuses on characterization of the highly complex tight junctions (TJs) of the BBB, which resemble epithelial TJs (Kniesel et al., 1994; Liebner et al., 2000b), and the unique parallel running TJ strands of the BCSFB (Engelhardt et al., 2001; Wolburg and Paulus, 2010). Yet, formation of TJs generally requires the existence of adherens junctions (AJs), and central to the organization of dynamic junctions is the continuous crosstalk between components of AJs and TJs, a fact often neglected by researchers studying the BBB and the BCSFB. AJs do certainly exist in these barriers and are established between neighboring cells by the homophilic interaction between the transmembrane proteins vascular endothelial cadherin (VE-cadherin) and epithelial cadherin (E-cadherin) in CNS endothelial and choroid plexus epithelial cells, respectively (Vorbrodt and Dobrogowska, 2003). TJs and AJs are considered to have distinct functions. TJs regulate the diffusion of solutes and ions through the paracellular route, which is referred to as their “gate” function. TJs also establish a “fence” function by limiting the free movements of lipids and proteins from the apical and basolateral cell surfaces, thus contributing to cell polarity (Dejana et al., 2009). In addition to the TJs between two adjacent cells, a special molecularly distinct TJ has been described at tricellular contacts, where the corners of three endothelial or epithelial cells meet. Interestingly, these tricellular TJs exist in BBB endothelial cells and BCSFB epithelial cells (Iwamoto et al., 2014), suggesting that tricellular TJs may be required for full barrier function of both types of brain barriers. Before TJ formation, AJs initiate cell-to-cell contacts and promote their maturation, maintenance, and plasticity, and regulate tensile forces. Yet, far less is known about the underlying role of AJs in regulating dynamics of cell–contacts and the establishment of cell polarity at the brain barriers. In epithelial cells, including the choroid plexus epithelium, TJs are the most apical component of the junctional complex and thus clearly distinguishable from AJs. In endothelial cells, however, localization of TJs and AJs is more variable, and both junctional complexes appear intermingled, especially in brain endothelial cell-to-cell junctions (Schulze and Firth, 1993; Vorbrodt and Dobrogowska, 2003; Dejana et al., 2009). Given that endothelial AJs in peripheral vascular beds play an important role in the control of vascular permeability (Giannotta et al., 2013), the contribution of these junctions to the integrity of BBB junctions during development, normal physiology, and disease should be elucidated. This is underscored by recent evidence demonstrating that the TJ protein zonula occludens 1 (ZO-1) is also a central regulator of endothelial AJs (Tornavaca et al., 2015). Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the endothelial blood–brain barrier (BBB) and the epithelial blood– cerebrospinal fluid barrier (BCSFB), respectively. These barriers inhibit paracellular diffusion, thereby protecting the CNS from fluctuations in the blood. Studies of brain barrier integrity during development, normal physiology, and disease have focused on BBB and BCSFB tight junctions but not the corresponding endothelial and epithelial adherens junctions. The crosstalk between adherens junctions and tight junctions in maintaining barrier integrity is an understudied area that may represent a promising target for influencing brain barrier function. Brain barriers: Crosstalk between complex tight junctions and adherens junctions