The function of DKK3 in the ocular lens
Date
2022
Authors
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Publisher
University of Delaware
Abstract
In the United States, it is estimated that 45% of all deaths are caused by fibrotic disorders. Canonical Transforming growth factor ß (TGFß) signaling is considered the main driver of the fibrotic response, though there are other signaling pathways that contribute to the fibrotic response as well. Canonical Wnt signaling has been show to drive fibrosis both independently and synergistically with TGFß depending on the cell type and situation. Dickkopf Wnt signaling pathway inhibitors (DKKs) are a family of proteins that include DKK1, 2, 3 and 4, and are known to inhibit canonical Wnt signaling. Dkk3 is highly abundant in the lens epithelial cell of mice. Dkk3 is primarily described as a canonical Wnt signaling inhibitor, though new evidence suggests that it has influence on many other pathways. A mouse strain which has a full germline deletion of Dkk3 was used extensively to investigate Dkk3’s function in the eye, specifically the lens epithelial cells. While Dkk3 is the 15th most abundant mRNA in the lens epithelial cells, this study found very little change was present in the adult Dkk3 null mouse eye. However, when examining how the lens epithelial cells responded to trauma due to lens fiber cell removal it became apparent that Dkk3’s absence altered how lens epithelial cells responded to that physical trauma. Particularly, the null mouse had marked decreases in many markers which are upregulated in the WT lens epithelial cells when they are undergoing a fibrotic response. This suggests that Dkk3 is an actor in the complex system that drives and controls fibrosis in the lens epithelial cells. It is unclear whether Dkk3 is directly modulating canonical Wnt signaling, or if it is interacting with other pathways, such as canonical TGFß signaling, which Dkk3 has been demonstrated to independently influence in other cell types.
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Keywords
Fibrotic disorders, DKK3, Canonical Wnt signaling, TGFs, Canonical TGFs signaling, Ocular lenses