Abstract
ABSTRACTIn vertebrate lens, lens epithelial cells cover the anterior half of the lens fiber core. Lens epithelial cells proliferate, move posteriorly and start to differentiate into lens fiber cells at the lens equator. Although FGF signaling promotes this equatorial commencement of lens fiber differentiation, the underlying mechanism is not fully understood. Here, we show that lens epithelial cells abnormally enter lens fiber differentiation without passing through the equator in zebrafish vps45 mutants. VPS45 belongs to the Sec1/Munc18-like protein family and promotes endosome trafficking, which differentially modulates signal transduction. Ectopic lens fiber differentiation in vps45 mutants does not depend on FGF, but is mediated through activation of TGFβ signaling and inhibition of canonical Wnt signaling. Thus, VPS45 normally suppresses lens fiber differentiation in the anterior region of lens epithelium by modulating TGFβ and canonical Wnt signaling pathways. These data indicate a novel role of endosome trafficking to ensure equator-dependent commencement of lens fiber differentiation.
Highlights
In the vertebrate lens, lens epithelium covers the anterior half of the lens fiber core
Retinal lamination was grossly normal in rw341 mutants (Fig. 1E), retinal stem cells located in the ciliary margin were swollen (Fig. S1A)
As epithelial-mesenchymal transition (EMT) is associated with disruption of monolayered lens epithelium in anterior subcapsular cataracts (ASCs) (Eldred et al, 2011), we examined expression of an EMT marker α-smooth muscle actin (αSMA), using a zebrafish transgenic line, Tg[acta2:EGFP], that expresses EGFP under control of the αSMA/acta2 gene promoter (Whitesell et al, 2014)
Summary
Lens epithelium covers the anterior half of the lens fiber core. Lens epithelial cells proliferate and move towards the periphery of the lens epithelium, called the equator (Hanna and O’Brien, 1961). Lens epithelial cells start to differentiate into lens fiber cells (McAvoy, 1978). Fibroblast growth factor (FGF) plays an important role in cell proliferation and differentiation in mammalian lens. Four decades ago it was discovered that co-culturing rat lens epithelial explants with the retina promotes lens fiber cell differentiation, suggesting that secreted molecules emanating from the retina promote lens fiber differentiation (McAvoy, 1980; McAvoy and Fernon, 1984). Application of FGF to lens epithelium induces cell proliferation at a low dose and lens fiber cell differentiation at a high dose, suggesting that FGF regulates multiple steps of lens fiber differentiation in a Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Tancha 1919-1, Onna, Okinawa 098-0945, Japan
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