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Hunter Lee Angle, Adam Faranda, Samuel G Novo, Aarthi Krishnan, Melinda K Duncan; The potential role of DKK3 in the pathogenesis of posterior capsular opacification. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2062.
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© ARVO (1962-2015); The Authors (2016-present)
Posterior capsular opacification (PCO) is the leading complication of cataract surgery (PCS) While it is established that canonical TGFβ/pSMAD3 signaling is a major driver of PCO, we have previously reported that canonical Wnt signaling also upregulates in lens epithelial cells (LECs) PCS. As TGFβ and canonical Wnt signaling can synergize to drive fibrosis in other systems, we sought to understand the mechanisms by which Wnt signaling upregulates in LECs PCS.
The transcriptome of adult mouse LECs was profiled by RNAseq either immediately after lens fiber cell removal or 6, 24, 48, or 120 hours later. The corneal transcriptome of adult mice was also investigated via RNAseq. Mice lacking the DKK3 gene were obtained from the Riken mouse resource, and bred to mice harboring a transgenic canonical Wnt signaling reporter (WntR) whose read out is nuclear localized Green fluorescent protein (GFP). Adult eyes were isolated from mice heterozygous for WntR and either wildtype (WT) or homozygous for the DKK3 null allele. The activity of WntR was assess by confocal immunofluorescent staining for GFP, which was quantitated using FiJi ImageJ.
The mRNA levels of DKK3, a known Pax6 target gene, are high in naïve LECs and downregulate by 6hrs PCS and remain low in these cells through 120 hours PCS. However, while DKK3 was first described as an inhibitor of canonical Wnt signaling, LECs lacking DKK3 do not upregulate canonical Wnt signaling suggesting that Dkk3 downregulation in LECs PCS is not responsible for the upregulation of canonical Wnt signaling we have previously found to occur in LECs PCS. Notably, DKK3 mRNA levels are also very high in the adult mouse cornea, and DKK3 null mice exhibited a 50% reduction in canonical Wnt reporter activity compared to wildtype (p=0.03) suggesting that DKK3 activates canonical Wnt reporter signaling in the cornea as has been reported in other cell types.
While DKK3 is not essential to keep canonical Wnt signaling low in the lens epithelium, it still may regulate normal lens biology and/or PCO as its high levels in the healthy lens rapidly decrease after cataract surgery and this protein has been reported to modulate both TGFβ and NFkappaB signaling in other systems. This hypothesis is actively being tested by transcriptome profiling of the DKK3 null lens.
This is a 2021 ARVO Annual Meeting abstract.
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