Figure 1

Schematic representation of TJ modulation by the NVU. (a) The basal lamina protein agrin increases claudin-5 (Cld5) and occludin expression [92]; (b) Aquaporin-4 density, regulated by agrin, stabilizes TJ complexes through ZO-1 expression [93]; (c) β1-integrin engagement stabilizes Cld5 localization at the TJ [94]; (d) astrocyte/pericyte-secreted TGF-β induces Cld5 transcription through activation of Smad transcription factor [91]; (e) Shh enhances expression of TJ proteins via its membrane receptor Ptch1/Smo and the transcription factor Gli-1 [95]; (f) Endothelial PDGF-β recruits pericytes which stabilize BBB phenotype [90]; (g) Wnt 7a/7b proteins, via their membrane receptors Frizzled-4 associated to LRP5/6, induce Cld3 transcription through stabilization of β-catenin [96]; (h i j) Angiopoietin-1 (Ang1), via its membrane receptor Tie2, enhances VE-Cadherin clustering and Cld5 transcription through inhibition of FoxO1 activity by PI3K and β-catenin sequestration [83, 97] ; (k) VE-Cadherin engagement recruits CCM1 and the polarity complex (PCP) leading to TJ stabilization [98].