Endothelial Cell–Specific Inactivation of TSPAN12 (Tetraspanin 12) Reveals Pathological Consequences of Barrier Defects in an Otherwise Intact Vasculature

Abstract

Supplemental Digital Content is available in the text.

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

“…Norrin promotes BRB formation by the induction of tight junction organization. In retinal endothelial cells of norrin, FZD4, LRP5 or TSPAN12 knockout mice, the fenestration marker PLVAP was increased, whereas claudin-5 staining at the cell border was decreased (5,10,29,31,49,63,64), thus indicating that in the absence of norrin signaling both, paracellular and transcellular routes are compromised. In addition, recent studies using siRNA suggest that PLVAP contributes to VEGF-induced permeability (65).…”

“…The importance of TSPAN12 co-activator in norrin signaling has recently emerged (8,29). Gene deletion studies of TSPAN12 demonstrate reduced retinal capillary development and loss of barrier properties in adult mice with a phenotype similar to aspects of humans with diabetic retinopathy including increased solute accumulation and cystoid edema (29).…”

“…The importance of TSPAN12 co-activator in norrin signaling has recently emerged (8,29). Gene deletion studies of TSPAN12 demonstrate reduced retinal capillary development and loss of barrier properties in adult mice with a phenotype similar to aspects of humans with diabetic retinopathy including increased solute accumulation and cystoid edema (29). Consistent with the role of TSPAN12 as a co-activator for norrin signaling through FZD4, the studies described herein suggest a novel mechanism in which VEGF primes endothelial cells to respond to norrin by regulating the specific expression of TSPAN12 through translational control and by inducing its membrane accumulation in a MEK/ERK-dependent manner.…”

“…Loss of norrin or TSPAN12 in mouse retina reveals a phenotype that resembles some of the pathological features of diabetic retinopathy. Retinas from mice with norrin gene deletion showed formation of cystoid edema, neovascularization and inflammation (37), while endothelial-specific loss of TSPAN12 induces cystoid edema formation and basement membrane collagen IV deposition (29). Other studies suggest that norrin (38) and β-catenin (39) increase in diabetes as determine in retinal sections of postmortem human eyes.…”

“…The retinal hypo vascularization disorders, referred to as familial exudative vitreopathy (FEVR), are caused by mutations in the genes encoding for norrin receptor FZD4 (16)(17)(18), and co-receptors LRP5 (19)(20)(21)(22), TSPAN12 (16,17,23,24), β-catenin (25,26) and some norrin mutations (27). The hypo vascular phenotype observed in both Norrie and FEVR diseases has been recapitulated in knockout mice models of norrin or the FZD4 receptor complex (1,5,8,(28)(29)(30)(31)(32)(33)(34), in which retinal vascular growth, mural cell recruitment, endothelial differentiation and barrier properties, are affected as a consequence of a low Sox7, Sox17 and Sox18 gene expression (35), or due an increased expression of the Wnt signaling inhibitor APCDD1 (36). Importantly, these retinas show high retinal vascular permeability that correlates with reduced border immunostaining of the tight junction protein claudin-5 and increased expression of the transcytosis marker PLVAP, a phenotype that can be reversed by the expression of stabilized β-catenin (5).…”