Frizzled 4 Is Required for Retinal Angiogenesis and Maintenance of the Blood-Retina Barrier

Paes, Kim; Wang, Ernest; Henze, Kathy; Vogel, Peter; Read, Robert W.; Suwanichkul, Adisak; Kirkpatrick, Laura L.; Potter, David; Newhouse, Matthew M.; Rice, Dennis S.

doi:10.1167/iovs.10-7146

Cited by 63 publications

(56 citation statements)

References 26 publications

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“…It would be of great interest to determine whether alterations in canonical Wnt signaling play a role in pathologic BBB breakdown, as observed in the contexts of neuroinflammation, stroke, and trauma (Obermeier et al, 2013). Defining the molecules and pathways that control BBB integrity also suggests potential strategies for transient and/or localized modulation of BBB integrity to enhance CNS drug delivery (Paes et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling

2014

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Summary Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G-protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a co-activator of Wnt7a-and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp co-receptor, and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific co-activator of canonical Wnt signaling.

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Section: Discussionmentioning

confidence: 99%

Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling

2014

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“…Using a function-blocking anti-FZ4 monoclonal antibody, Paes et al (63) have demonstrated disruption of the BRB following systemic mAb delivery in adult mice. Extrapolating from the jci.org Volume 124 Number 9 September 2014…”

Section: Methodsmentioning

confidence: 99%

Canonical WNT signaling components in vascular development and barrier formation

Zhou¹,

Wang²,

Tischfield³

et al. 2014

J. Clin. Invest.

278

330

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“…Stenman et al observed that mice lacking both Wnt7a and Wnt7b have neural tube hemorrhages as ventral blood vessel development is altered, with these vessels expressing lower levels of GLUT1 (Daneman et al, 2009;Stenman et al, 2008;. Norrin signaling through Frizzled 4 is required for retinal angiogenesis and defects in this pathway lead to retinal diseases including the Norrie disease and familial exudative vitreoretinopathy (Junge et al, 2009;Paes et al, 2011;Wang et al, 2012;Ye et al, 2009). Norrin is a TGF-beta family member with no homology to any Wnt ligands, but is able to active Frizzled4 and induce canonical Wnt signaling, suggesting a unique mechanism for activation of Wnt/beta-catenin pathway within retinal vessels.…”

Section: Wnt Pathwaymentioning

confidence: 99%

“…The pattern of vascular defects within the brain of Gpr124 -/-is very similar to that of Wnt7a -/-Wnt7b -/-embryos (Daneman et al, 2009;Stenman et al, 2008; It has also been shown that Wnt/beta-catenin signaling is required to maintain BBB integrity throughout life. Frizzled 4 deletion or the administration of anti-Frizzled 4 blocking antibody in adult mice leads to an increase PLVAP expression and BBB/blood-retinal barrier (BRB) permeability (Paes et al, 2011;Wang et al, 2012) and deletion of the expression or mutation of Norrin or…”

Section: Wnt Pathwaymentioning

confidence: 99%

Formation and maintenance of the BBB

Blanchette

Daneman

2015

Mechanisms of Development

193

140

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The central nervous system (CNS) is vascularized by a dense capillary network that is critical to deliver oxygen and nutrients, and remove carbon dioxide and waste products, from the neural tissue. These blood vessels contain a series of properties, termed the blood-brain barrier (BBB), which distinguishes them from vasculature in other tissues, enabling CNS vessels to stringently regulate the transfer of ions, molecules and cells between the blood and the tissue. This barrier is critical to maintain brain homeostasis which allows for proper neuronal function and also to protect the tissue from injury and disease and many neurological diseases are associated with BBB dysfunction, including traumatic brain injuries, Alzheimer's disease, stroke, epilepsy, and multiple sclerosis. Therefore, a better understanding of the mechanisms controlling the development of the BBB may lead to improved comprehension of the pathophysiology of these diseases, and further aid in the identification of targets to modulate the barrier to treat different neurological diseases. Many of the properties of the BBB are possessed by the endothelial cells that form the walls of the blood vessels but are acquired through a series of complex cellular interactions with the microenvironment throughout its development. We will review what is known about the induction and regulation of BBB properties during development.

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Frizzled 4 Is Required for Retinal Angiogenesis and Maintenance of the Blood-Retina Barrier

Cited by 63 publications

References 26 publications

Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling

Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling

Canonical WNT signaling components in vascular development and barrier formation

Formation and maintenance of the BBB

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