Lens arises from ectoderm situated next to the optic vesicles. By thickening and invaginating, the ectoderm forms the lens vesicle. Growth factors are key regulators of cell fate and behavior. Current evidence indicates that FGFs and BMPs are required to induce lens differentiation from ectoderm. In the lens vesicle, posterior cells elongate to form the primary fibers whereas anterior cells differentiate into epithelial cells. The divergent fates of these embryonic cells give the lens its distinctive polarity. There is now compelling evidence that, at least in mammals, FGF is required to initiate fiber differentiation and that progression of this complex process depends on the synchronized and integrated action of a number of distinct growth factor-induced signaling pathways. It is also proposed that an antero-posterior gradient of FGF stimulation in the mammalian eye ensures that the lens attains and maintains its polarity and growth patterns. Less is known about differentiation of the lens epithelium; however, recent studies point to a role for Wnt signaling. Multiple Wnts and their receptors are expressed in the lens epithelium, and mice with impaired Wnt signaling have a deficient epithelium. Recent studies also indicate that other families of molecules, that can modulate growth factor signaling, have a role in regulating the ordered growth and differentiation of the lens.

The vertebrate lens has a distinct polarity and structure that are regulated by growth factors resident in the ocular media. Fibroblast growth factors, in concert with other growth factors, are key regulators of lens fiber cell differentiation. While members of the transforming growth factor (TGFβ) superfamily have also been implicated to play a role in lens fiber differentiation, inappropriate TGFβ signaling in the anterior lens epithelial cells results in an epithelial-mesenchymal transition (EMT) that bears morphological and molecular resemblance to forms of human cataract, including anterior subcapsular (ASC) and posterior capsule opacification (PCO; also known as secondary cataract or after-cataract), which occurs after cataract surgery. Numerous in vitro and in vivo studies indicate that this TGFβ-induced EMT is part of a wound healing response in lens epithelial cells and is characterized by induced expression of numerous extracellular matrix proteins (laminin, collagens I, III, tenascin, fibronectin, proteoglycans), intermediate filaments (desmin, α-smooth muscle actin) and various integrins (α2, α5, α7B), as well as the loss of epithelial genes [Pax6, Cx43, CP49, α-crystallin, E-cadherin, zonula occludens-1 protein (ZO-1)]. The signaling pathways involved in initiating the EMT seem to primarily involve the Smad-dependent pathway, whereby TGFβ binding to specific high affinity cell surface receptors activates the receptor-Smad/Smad4 complex. Recent studies implicate other factors [such as fibroblast growth factor (FGFs), hepatocyte growth factor, integrins], present in the lens and ocular environment, in the pathogenesis of ASC and PCO. For example, FGF signaling can augment many of the effects of TGFβ, and integrin signaling, possibly via ILK, appears to mediate some of the morphological features of EMT initiated by TGFβ. Increasing attention is now being directed at the network of signaling pathways that effect the EMT in lens epithelial cells, with the aim of identifying potential therapeutic targets to inhibit cataract, particularly PCO, which remains a significant clinical problem in ophthalmology.

No abstract

This review gives a brief account of the main processes of lens development, including induction, morphogenesis, differentiation and growth. It describes what is known about the molecules and mechanisms that control and regulate these processes. Some of the recent progress made in understanding the molecular basis of lens development is highlighted along with some of the challenging areas for future research.

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.

Intestinal folds of adult Xenopus laevis are formed by the proliferation of groups of cells in the tadpole epithelium a t metamorphosis. As the folds increase in number and in height, mitoses become confined to the troughs and a gradient of decreasing mitotic activity from troughs to crests is formed. This pattern of cell proliferation was confirmed in autoradiographic studies with 13Hlthymidine. Migration of cells from the fold troughs to the fold crests was also demonstrated by thymidine autoradiography and the epithelium renewal time was approximately 16 days. Thus cell proliferation and cell specialisation in the small intestinal epithelium of adult X laevis are inversely correlated.

No abstract

Growth factors play key roles in influencing cell fate and behaviour during development. The epithelial cells and fibre cells that arise from the lens vesicle during lens morphogenesis are bathed by aqueous and vitreous, respectively. Vitreous has been shown to generate a high level of fibroblast growth factor (FGF) signalling that is required for secondary lens fibre differentiation. However, studies also show that FGF signalling is not sufficient and roles have been identified for transforming growth factor-b and Wnt/Frizzled families in regulating aspects of fibre differentiation. In the case of the epithelium, key roles for Wnt/b-catenin and Notch signalling have been demonstrated in embryonic development, but it is not known if other factors are required for its formation and maintenance. This review provides an overview of current knowledge about growth factor regulation of differentiation and maintenance of lens cells. It also highlights areas that warrant future study.