WNT/Frizzled signaling in eye development and disease

Abstract

The canonical Wnt/Fzd signaling pathway is highly conserved among various species. Increasing evidence is accumulating for non-canonical Wnt signaling pathways, analogous to those discovered in Drosophila, being operative in vertebrates. Similarly, the networks of genes involved in eye development show significant conservation during evolution. The amenability of Drosophila for genetic manipulation and analysis of ocular phenotypes has delivered a great deal of information about the roles of the Wnt/Fzd signaling pathways at various stages of ocular development and growth, particularly in regulating the formation and size of the eye field, cell proliferation, polarity and differentiation. In addition to the numerous recent studies that have identified the expression of various components of these signaling pathways in the developing vertebrate eye, functional studies have revealed significant parallels in the way that Wnt/Fz signals regulate the formation of the vertebrate eye field and also the proliferation and differentiation of cells, particularly in the lens and retina. Significant advances have also recently been made in identifying mutations in these signaling pathways that underlie or contribute to various ocular diseases such as exudative vitreoretinopathy, retinal degenerations, cataract, ocular tumors and various congenital ocular malformations. Combined with the mechanistic studies in vertebrate and invertebrate models, these studies point to important functional roles for Wnt/Fzd pathways in the human eye. Further investigation of how these pathways function during eye development and growth may yield important insights into novel therapeutic approaches to treat or prevent diseases that cause blindness.

Revisiting the role of erythropoietin for treatment of ocular disorders

“…The Wnt signaling pathway has an important role in the developmental processes of the eye field, lens, and retina. [16][17][18] As presented in Figure 3, binding of EPO to heterodimeric EPOR/βcR complex, leads to binding of Wnt to the Frizzled transmembrane receptors and subsequent inhibition of the β-catenin phosphorylation by glycogen synthase kinase (GSK)-3β. Activated β-catenin then escapes from proteasomal destruction , the outer nuclear layer (ONL), the outer plexiform layer (OPL), the inner nuclear layer (INL), the inner plexiform layer (IPL), and the ganglion cell layer.…”

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…14 Stabilized b-catenin then translocates into the nucleus, where it associates with T cell factor/lymphoid enhancer factor to activate target gene transcription. 8,12,15,16 In FEVR, lack of any one of LRP5/Frizzled4/TSPAN12/ Norrin causes deficient canonical Wnt signaling pathway at the ligand/receptor level, which allows the GSK3 complex to increase b-catenin degradation, resulting in eventual suppression of physiological vessel growth in the retina. 2,17 Both Sox17 and claudin5 were down-regulated in Wnt-deficient retinal vessels and were suggested to play a potential role in mediating vascular formation in FEVR retina, 11,18 although the exact underlying molecular mechanisms of Wnt signalingemediated retinal vascular defects are not completely understood yet.…”

Wnts as ligands: processing, secretion and reception

“…In the most well understood 'canonical' Wnt signaling pathway, Wnt binding to Frizzled and LRP5/6 co-receptors induces b-Catenin protein stabilization and entry into the nucleus where it affects the transcription of target genes. Because uncontrolled canonical Wnt signaling is a hallmark of cancer and other degenerative diseases, understanding the ways in which the pathway is regulated is of critical importance (Polakis, 2000;Clevers and Batlle, 2006;de Iongh et al, 2006;Fox and Dharmarajan, 2006;Krishnan et al, 2006).…”