Wnt signaling is required for organization of the lens fiber cell cytoskeleton and development of lens three-dimensional architecture

Abstract

How an organ develops its characteristic shape is a major issue. This is particularly critical for the eye lens as its function depends on having appropriately ordered three-dimensional cellular architecture. Recent in vitro studies indicate that Wnt signaling plays key roles in regulating morphological events in FGF-induced fiber cell differentiation in the mammalian lens. To further investigate this the Wnt signaling antagonist, secreted frizzled-related protein 2 (Sfrp2), was overexpressed in lens fiber cells of transgenic mice. In these mice fiber cell elongation was attenuated and individual fibers exhibited irregular shapes and consequently did not align or pack regularly; microtubules, microfilaments and intermediate filaments were clearly disordered in these fibers. Furthermore, a striking feature of transgenic lenses was that fibers did not develop the convex curvature typically seen in normal lenses. This appears to be related to lack of protrusive processes that are required for directed migratory activity at their apical and basal tips as well as for the formation of interlocking processes along their lateral margins. Components of the Wnt/Planar Cell Polarity (PCP) pathway were downregulated or inhibited. Taken together this supports a role for Wnt/PCP signaling in orchestrating the complex organization and dynamics of the fiber cell cytoskeleton.

Understanding the role of growth factors in embryonic development: insights from the lens

“…This is related to a loss of ability of fibres to re-orient and undergo directed cell migration so that the anterior and posterior tips of fibres from different segments do not meet appropriately to form the characteristic Y-shaped sutures at the lens poles. Consistent with the involvement of Wnt/PCP signalling in regulating this process, components of this pathway are downregulated in these transgenic lenses [42]. Taken together, these studies indicate a role for Wnt/ PCP signalling in coordinating the precise alignment and orientation of fibres that is required during their differentiation.…”

“…In lenses of Loop-tail (Vangl2 mutation) and Crash (Celsr1 mutation) mice, the alignment and orientation of fibres is perturbed so that normal Y-shaped sutures do not form [84]. In addition, transgenic mice that overexpress Sfrp2, a known regulator of Wnt signalling, in lens fibres show that their alignment and packing is disrupted [42]. A striking feature of these lenses is that fibres do not develop the convex curvature typically seen in normal lenses ( figure 6).…”

Integrin-Linked Kinase Deletion in the Developing Lens Leads to Capsule Rupture, Impaired Fiber Migration and Non-Apoptotic Epithelial Cell Death

“…Interestingly, the same fiber migration defect is observed when the Rho GTPase-dependent signaling pathways are disturbed in the lens either by over-expression of a negative regulator, 72,73 disruption of the upstream non-canonical Wnt/ PCP pathway, 74 or following deletion of an adapter protein linked to this pathway. 68 In a manner similar to Rho GTPases, ILK has a pivotal role in regulating actin cytoskeletal dynamics and cell adhesive interactions, 72 events presumed to enable migration of the fibers along the anterior epithelium.…”

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

“…Sfrp proteins are required for Wnt diffusion, activation, canonical signaling, and proper tissue differentiation; their effects on Wnt signaling are dependent on their concentration or Wnt ligands present in tissue (23, 26, 42, 63a). For example, Sfrp-2 can enhance activation of the canonical Wnt pathway (17,64,66) while inhibiting the noncanonical pathway, resulting in abnormal cell alignment and shape (12). Sfrp-2 can inhibit BMP-4 expression and prevent programmed cell death (22).…”