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Ross F Collery, Brian A Link; Expression of soluble Bmp antagonists from the zebrafish RPE leads to eye enlargement and myopia. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5844.
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© ARVO (1962-2015); The Authors (2016-present)
Bmp signaling is involved in early eye development, but negatively regulates growth in the adult eye. bugeye zebrafish lacking the large endocytic receptor Lrp2, which is expressed in the RPE and binds Bmp4, show grossly enlarged eyes and high myopia. Here we investigate the effects of expressing antagonists to Bmp (Nog3, Grem2) as well as a soluble domain of Lrp2 found to bind Bmp4, and analyze the effects on eye size and refractive state.
An RPE-specific promoter was used with the bipartite Gal4/UAS system to express Nog3, Grem2, and the first LDLA1 domain of Lrp2. Zebrafish expressing transgenes and control siblings were imaged using a Bioptigen SD-OCT system at 2 months of age, measuring eye axial length, retinal radius and lens diameters. Using these metrics, eye sizes were normalized and degrees of refractive errors were calculated.
Zebrafish expressing Nog3 from the RPE showed enlarged eyes and increased myopia compared to their control siblings. lrp2-/- zebrafish show enlarged and myopic eyes relative to wild-types, and this phenotype is exacerbated with RPE-driven Nog3 expression. Similarly, expression of Grem2 from the RPE also increased eye size and degree of myopia, but only in lrp2-/- zebrafish. Finally we demonstrated that Bmp4 binds in vivo to the LDLA1 extracellular domain of Lrp2, and found that expression of soluble Lrp2 (LDLA1)-eGFP from the RPE also increased eye size and degree of myopia.
Bmp antagonists exert their effect by binding extracellular ligands and prevent them from activating their cognate receptors, thus modulating signaling. We propose that overexpression of Bmp antagonists in the RPE leads to a large, myopic eye phenotype in part by inhibiting Bmp signaling. In ongoing experiments, we will investigate whether Lrp2 is endogenously cleaved to generate a soluble LDLA1-containing ectodomain, and examine whether such putative processing alters its effects on Bmp signaling during emmetropization and with myopia.
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