The duality of β-catenin function: A requirement in lens morphogenesis and signaling suppression of lens fate in periocular ectoderm

Abstract

In the current analysis, we have investigated both the cytoskeletal and signaling roles of beta-catenin during the early phases of lens development using conditional loss- and gain-of-function strategies. Conditional loss of beta-catenin in the presumptive lens does not perturb the normal sequential appearance of lens fate markers but results in a dramatic failure of the coordinated epithelial cell behavior that constitutes lens morphogenesis. Similarly, loss-of-function for Lrp6, the Wnt pathway coreceptor expressed in the eye primordium, does not prevent expression of lens induction markers. Surprisingly, conditional deletion of beta-catenin in periocular ectoderm results in the formation of Prox-1 and beta-crystallin-positive ectopic lentoid bodies. Combined with the observation that the Wnt pathway reporter TOPGAL is expressed in nasal periocular ectoderm, these data suggest that, in this location, the canonical Wnt signaling pathway normally suppresses lens fate in favor of other structures. Consistent with this proposal, a dominant-active form of beta-catenin causes a loss of lens fate and a complete absence of lens development when expressed in the presumptive lens ectoderm.

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

“…Analyses of specific neural crest and neuroectoderm markers would reveal this uncertainty. In agreement, loss of b-catenin activity in the presumptive lens and extraocular ectoderm using the Lens-Cre construct does not perturb lens fate decision, but leads to formation of small ectopic lentoids expressing Pax6 and crystallin proteins in the extraocular ectoderm [63,64]. The overall conclusion is that between gastrula stages and lens placodal stages Wnt activity restricts caudal expansion of lens formation (figure 3).…”

“…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lens cells in chick explants still upregulate the lens markers L-Maf and d-crystallin (Sjö dal and Gunhaga 2006, unpublished data).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.…”

“…In LacZ reporter mouse lines, which express LacZ in response to activation of the canonical Wnt pathway [61,62] there is no indication of X-gal staining, i.e. Wnt activity, in the lens region at E8.5-E15.5 [63,64]. 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).…”

Signaling during lens regeneration

“…An important aspect to both lens development and lens regeneration is the differentiation of lens fiber cells. In the case of lens development, the Wnt/β-catenin signaling pathway appears essential for the differentiation of the lens epithelium into lens fiber cells [34][35][36]. Mice with a homozygous null mutation in the lrp6 co-receptor gene are unable to fully undergo differentiation of the lens epithelium [35].…”

“…Dickkopfs antagonize the pathway by binding to the LRP co-receptor and preventing the stabilization of the β-catenin complex. A study examining β-catenin function in lens development found that loss of β-catenin function in the periocular ectoderm of embryonic mice results in ectopic lentoid body formation [36].…”