Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Robitaille, Johane; Macdonald, M. L. E.; Kaykas, Ajamete; Sheldahl, Laird C; Zeisler, Jutta; Dubé, Marie‐Pierre; Zhang, Linhua; Singaraja, Roshni R.; Guernsey, Duane L.; Zheng, Binyou; Siebert, Lee; Hoskin-Mott, A; Trese, Michael T.; Pimstone, Simon N.; Shastry, Barkur S.; Moon, Randall T.; Hayden, Michael R.; Goldberg, Y P; Samuels, Mark E.

doi:10.1038/ng957

Cited by 402 publications

(312 citation statements)

References 27 publications

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“…Importantly, mutations in human Fz-4 are linked to familial exudative vitreoretinopathy (FEVR), providing the first direct evidence of the connection between Wnt signaling and a human vascular disorder (28). Consistently, the deletion mutant of fz-4 displays defective angiogenesis resembling FEVR (29). FEVR is a hereditary ocular disorder characterized by defective peripheral retinal vascularization, retinal detachment, and leaky vasculature that bleeds and exudes.…”

Section: Wnts In Vascular Biologymentioning

confidence: 79%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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SummaryThe Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists.

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Section: Wnts In Vascular Biologymentioning

confidence: 79%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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“…Mutations in the Frizzled-4 gene are correlated with angiogenesis-related disorders in humans. Mutations in Frizzled-4 have been linked to familial exudative vitreoretinopathy (FEVR), a disorder of the retinal vasculature (Robitaille et al, 2002). Similar disruption of the vasculature is seen in patients with mutations in a novel Frizzled ligand, Norrin, and retinal vascular development likely depends on Norrin/Frizzled-4 interactions (Xu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Similar disruption of the vasculature is seen in patients with mutations in a novel Frizzled ligand, Norrin, and retinal vascular development likely depends on Norrin/Frizzled-4 interactions (Xu et al, 2004). Frizzled-4 can activate the noncanonical Wnt pathway through a mechanism involving calcium/ calmodulin kinase II (CamKII) and PKC activation (Robitaille et al, 2002). We speculate that Frizzled-4 may also utilize Wnt5a as a ligand to regulate vascular development.…”

Section: Discussionmentioning

confidence: 99%

“…Wnt signaling has been linked to a human vascular disorder by the finding that Frizzled-4, which might be involved in signaling via both canonical and noncanonical pathways, is critical for proper retinal vascular development (Robitaille et al, 2002;Xu et al, 2004). Whether one or both of these two pathways is critical for retinal angiogenesis is still not clear.…”

Section: Introductionmentioning

confidence: 99%

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Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

Masckauchán

Agalliu

Vorontchikhina

et al. 2006

MBoC

192

162

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Wnts are lipid-modified secreted glycoproteins that regulate diverse biological processes. We report that Wnt5a, which functions in noncanonical Wnt signaling, has activity on endothelial cells. Wnt5a is endogenously expressed in human primary endothelial cells and is expressed in murine vasculature at several sites in mouse embryos and tissues. Expression of exogenous Wnt5a in human endothelial cells promoted angiogenesis. Wnt5a induced noncanonical Wnt signaling in endothelial cells, as measured by Dishevelled and ERK1/2 phosphorylation, and inhibition of canonical Wnt signaling, a known property of Wnt5a. Wnt5a induced endothelial cell proliferation and enhanced cell survival under serum-deprived conditions. The Wnt5a-mediated proliferation was blocked by Frizzled-4 extracellular domain. Wnt5a expression enhanced capillary-like network formation, whereas reduction of Wnt5a expression decreased network formation. Reduced Wnt5a expression inhibited endothelial cell migration. Screening for Wnt5a-regulated genes in cultured endothelial cells identified several encoding angiogenic regulators, including matrix metalloproteinase-1, an interstitial collagenase, and Tie-2, a receptor for angiopoietins. Thus, Wnt5a acts through noncanonical Wnt signaling to promote angiogenesis.

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“…Conserved residues in ICL1-3 and the carboxy-terminal domain in the intracellular space are also indicated, with invariable residues among all FZD proteins in bold. ( Ã above the letter) Missense mutations found in Drosophila Dfz1 ) and human FZD4 (Robitaille et al 2002); (underlined) residues tested via double alanine substitution scanning mutagenesis in FZD5 (Cong et al 2004b a "thumb" plus an "index finger" to grab/pinch the FZD8CRD globular structure on two opposite sides, without changing FZD8CRD conformation (Fig. 1D).…”

Section: The Fzd Extracellular Domain and Wnt Binding: The Wnt8-fzd8cmentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

495

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Cited by 402 publications

References 27 publications

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

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