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Thuzar Thein, Jimmy de Melo, Cristina Zibetti, Seth Blackshaw; Control of lens fiber development by Lhx2-regulated neuroretinal Fgfs. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4835. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Fibroblast growth factor (FGF) signaling is an essential regulator of lens epithelial cell proliferation and fiber cell differentiation. However, the identities of these Fgf factors, their source tissue, and the genes that regulate their synthesis are not well-characterized. In this study, we investigated the role of neuroretinal Lhx2 and Fgf factors in lens development.
Transgenic mice, Chx10-Cre and Pdgfrα-Cre, were used to delete Lhx2 and to overexpress Fgf10. Microarray, RNA-seq and qPCR analysis were conducted to investigate gene expression changes in these mice. ChIP-qPCR was performed to characterize Lhx2’s target genes. Immunohistochemistry and in situ hybridization were carried out to assess changes in morphology and molecular marker expression in these transgenic animals.
We have found that Chx10-Cre; Lhx2F/F mice, which selectively lacked Lhx2 expression in neuroretina beginning at E10.5, showed an early arrest in lens fiber development along with severe microphthalmia and retinal disorganization. When Lhx2 was deleted in late retinal progenitors and Muller glial precursors using Pdgfrα-Cre, these mice developed early onset cataract and subsequent lens degeneration. Both mutants showed reduced expression of multiple neuroretinal-expressed FGFs in neuroretina, and likewise showed reduced expression of canonical FGF target genes in both the neuroretina and lens. When FGF expression was selectively restored in Lhx2-deficient neuroretina of Chx10-Cre; Lhx2F/F mice using a CAG-lox-stop-lox-Fgf10 transgene, we observed a dramatic rescue of the defects in lens but not in neuroretinal development.
Our data demonstrate that neuroretina-derived FGF factors are both necessary and sufficient to drive lens fiber development in vivo.
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