A role for Wnt/β-catenin signaling in lens epithelial differentiation

Abstract

The differentiation of epithelial cells and fiber cells from the anterior and posterior compartments of the lens vesicle, respectively, give the mammalian lens its distinctive polarity. While much progress has been made in understanding the molecular basis of fiber differentiation, little is known about factors that govern the differentiation of the epithelium. Members of the Wnt growth factor family appear to be key regulators of epithelial differentiation in various organ systems. Wnts are ligands for Frizzled receptors and can activate several signaling pathways, of which the best understood is the Wnt/beta-catenin pathway. The presence of LDL-related protein coreceptors (LRPs) 5 or 6 has been shown to be a requirement for Wnt signaling through the beta-catenin pathway. To access the role of this signaling pathway in the lens, we analyzed mice with a null mutation of lrp6. These mice had small eyes and aberrant lenses, characterized by an incompletely formed anterior epithelium resulting in extrusion of the lens fibers into the overlying corneal stroma. We also showed that multiple Wnts, including 5a, 5b, 7a, 7b, 8a, 8b, and Frizzled receptors 1, 2, 3, 4, and 6, were detected in the lens. Expression of these molecules was generally present throughout the lens epithelium and extended into the transitional zone, where early fiber elongation occurs. In addition to both LRP5 and LRP6, we also showed the expression of other molecules involved in Wnt signaling and its regulation, including Dishevelleds, Dickkopfs, and secreted Frizzled-related proteins. Taken together, these results indicate a role for Wnt signaling in regulating the differentiation and behavior of lens cells.

The lens: a classical model of embryonic induction providing new insights into cell determination in early development

“…Consistently, even in the presence of Wnt inhibitors prospective lens cells in chick explants still upregulate the lens markers L-Maf and d-crystallin (Sjö dal and Gunhaga 2006, unpublished data). Finally, in mice, individual deletions of two Wnt co-receptors, Lrp5 and Lrp6 required for Wnt canonical signalling, do not perturb lens fate determination [64][65][66]. Although, a double knock-out of Lrp5 and Lrp6 would determine whether these co-receptors may act redundantly during early lens specification, it seems unlikely that such double mutants would exhibit a lens phenotype, since the above results clearly provide evidence that Wnt signals are not required for lens fate specification.…”

Expression patterns of Wnt genes during development of an anterior part of the chicken eye

“…For over 20 years, it was believed that fibroblast growth factors (FGFs) were the major regulators of lens fiber cell differentiation. However, recent data imply that the cooperative action of three different signaling pathways (FGF, BMP, and WNT) can control lens fiber cell differentiation, but the exact identity of the ligands remains unknown (BeleckyAdams et al, 2002;Stump et al, 2003;de Iongh et al, 2004;Lyu and Joo, 2004;Lovicu and McAvoy, 2005).…”

“…Second, mice lacking either of the Frizzled co-receptors (LRP5 or LRP6) demonstrated abnormal eye development. LRP6 knockout mice were microophthalmic and had severe defects in their retinal, lens, and corneal development (Gong et al, 2001;Stump et al, 2003;Jiao et al, 2004;Toomes et al, 2004). In LRP5 knockout mice, the hyaloid vasculature did not regress and was retained throughout the lifetime of the mice (Gong et al, 2001).…”

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

“…Specifically, truncating mutations in APC are thought to alleviate blockade of ␤-catenin͞LEF transcriptional activity, thus promoting cell proliferation and inhibiting cellular differentiation (5). Consistent with a potential role for APC in abnormal eye development, the WNT͞␤-catenin signaling cascade is critical for specification of lens tissue and regulation of lens growth and differentiation (6,7). WNT signaling also plays a role in various aspects of retinogenesis (8 -10).…”