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Fatima Wazin, Frank J Lovicu; Spred: A regulator of lens epithelial cell proliferation and fiber differentiation.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):893. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The transparent and refractive properties of the ocular lens are dependent on its precise cellular architecture, established and maintained through coordinated epithelial cell proliferation and subsequent differentiation into fibers. These cellular processes are known to require MAPK/ERK1/2-signaling, that in turn is negatively regulated by members of the Spred family of proteins. As Spreds are expressed throughout lens morphogenesis, and have previously been shown to be required for early lens growth, we hypothesized that these proteins play a role in regulating lens epithelial cell proliferation and fiber differentiation.
Lens development was examined in murine embryos deficient for both Spred1 and Spred2 (Spred1/2null), from embryonic days E12.5-E16.5. The lens ocular phenotype was characterized with particular attention to changes in lens epithelial cell numbers, proliferation (using BrdU-incorporation) and fiber cell differentiation (including BrdU-tracking over 48 hrs).
Mice deficient for all alleles of Spred1/2 in the lens exhibited microphthalmia and severe lens epithelial defects (increased cell numbers and multilayering) from E12.5 to E16.5. This deficiency correlated with disruptions to epithelial membrane markers, as well as increased labeling for phosphorylated (active) ERK1/2. Interestingly, we revealed that the mitotic activity and rate of fiber differentiation was stable in lenses of Spred1/2 mutants when compared to control lenses, despite changes in the spatial arrangement of the BrdU-labeled cells. Unlike control lenses that had an even distribution of BrdU-labeling in both epithelial and early fiber cells 48 hr post BrdU-incorporation, BrdU-labeling in Spred1/2 mutant lenses was preferentially localized to the fiber cells, highlighting the directional fate of proliferative cells.
The lens requires Spreds for its early growth phase, specifically for the maintenance of its precise cellular architecture. This study provides a greater understanding of the key molecules that help regulate developmental processes leading to lens growth, and provides insights into developing strategies to preserve and even regenerate normal lens cell structure.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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