Beta-catenin signaling regulates barrier-specific gene expression in circumventricular organ and ocular vasculatures.

Yanshu Wang,Jeremy Nathans,Amir Rattner,John Williams,Mark F Sabbagh,Xiaowu Gu

doi:10.7554/elife.43257

Yanshu Wang, Jeremy Nathans + Show 4 more

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https://doi.org/10.7554/elife.43257

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Abstract

The brain, spinal cord, and retina are supplied by capillaries that do not permit free diffusion of molecules between serum and parenchyma, a property that defines the blood-brain and blood-retina barriers. Exceptions to this pattern are found in circumventricular organs (CVOs), small midline brain structures that are supplied by high permeability capillaries. In the eye and brain, high permeability capillaries are also present in the choriocapillaris, which supplies the retinal pigment epithelium and photoreceptors, and the ciliary body and choroid plexus, the sources of aqueous humor and cerebrospinal fluid, respectively. We show here that (1) endothelial cells in these high permeability vascular systems have very low beta-catenin signaling compared to barrier-competent endothelial cells, and (2) elevating beta-catenin signaling leads to a partial conversion of permeable endothelial cells to a barrier-type state. In one CVO, the area postrema, high permeability is maintained, in part, by local production of Wnt inhibitory factor-1.

Highlights

Throughout the body, capillaries exhibit tissue- and organ-specific specializations of structure and function (Aird, 2007a; Aird, 2007b; Potente and Makinen, 2017)
In the CNS, the blood-brain barrier (BBB) and blood-retina barrier (BRB) are characterized by numerous specializations in vascular endothelial cell (EC) structure and function, including elaboration of tight junctions, suppression of transcytotic pathways, and production of small molecule transporters and extrusion pumps (Daneman and Prat, 2015; Zhao et al, 2015). [See Table 1 for a list of abbreviations used in this paper.] The BBB/BRB program of EC differentiation is controlled, at least in part, by beta-catenin signaling that is activated by ligands Wnt7a, Wnt7b, and Norrin
The circumventricular organs (CVOs) and choroid plexus vasculatures are readily visualized in the wild type (WT) mouse brain by immunostaining for PLVAP, which is abundant in the vascular organ of the lamina terminalis (VOLT), median eminence (ME), subfornical organ (SFO), area postrema, pineal, anterior pituitary, posterior pituitary, and choroid plexus vasculatures but absent from the adjacent BBB-type CNS vasculature

Summary

Introduction

Throughout the body, capillaries exhibit tissue- and organ-specific specializations of structure and function (Aird, 2007a; Aird, 2007b; Potente and Makinen, 2017). [See Table 1 for a list of abbreviations used in this paper.] The BBB/BRB program of EC differentiation is controlled, at least in part, by beta-catenin signaling (canonical Wnt signaling) that is activated by ligands Wnt7a, Wnt7b, and Norrin. These ligands are produced by glia and neurons, and they activate receptors and co-receptors on the surface of ECs (Liebner et al, 2008; Stenman et al, 2008; Daneman et al, 2009; Wang et al, 2012; Zhou and Nathans, 2014; Zhou et al, 2014; Posokhova et al, 2015).

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