Control of Lens and Ciliary Epithelial Development by the LIM-homeodomain Transcription Factor Lhx2
Embargo until
2020-12-01
Date
2016-08-02
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Johns Hopkins University
Abstract
LIM-homeodomain transcription factor Lhx2 is an essential regulator of mammalian eye development. To further elucidate the role of Lhx2 in mammalian eye development, we studied the effects of deleting Lhx2 at different embryonic time points. Fibroblast growth factor (FGF) signaling is an essential regulator of lens epithelial cell proliferation and survival, as well as lens fiber cell differentiation. However, the identities of these FGF factors, their source tissue, and the genes that regulate their synthesis are unknown. We have found that Chx10-Cre;Lhx2lox/lox mice, which selectively lack Lhx2 expression in neuroretina from E10.5, showed an early arrest in lens fiber development along with severe microphthalmia. These mutant animals showed reduced expression of multiple neuroretina-expressed FGFs and canonical FGF-regulated genes in neuroretina. When FGF expression was genetically restored in Lhx2-deficient neuroretina of Chx10-Cre;Lhx2lox/lox mice, we observed a dramatic rescue of the defects in lens cell proliferation, survival and fiber differentiation. These data demonstrate that neuroretinal expression of Lhx2 and neuroretina-derived FGF factors are crucial for lens fiber development in vivo. To investigate the role of Lhx2 at later stages of lens development and maintenance, we deleted Lhx2 in late retinal progenitors and Muller glial precursors using three different Cre lines. The development of cataract was observed in all three of them, suggesting the role of Lhx2 in maintaining lens transparency. The ciliary epithelium is a bilayered secretory structure at the anterior segment of the eye. It is derived from neuroectoderm, which also gives rise to the neural retina and retinal pigment epithelium (RPE). Previous studies have shown that BMP, FGF, Notch and Wnt signaling all regulated the development of the ciliary body. As we have previously found that Lhx2 regulated Notch and FGF signaling, we investigated the role of Lhx2 in ciliary epithelial development. We found that Lhx2 also regulated BMP signaling and that conditional deletion of Lhx2 led to disruption of ciliary epithelial development. Thus, Lhx2 may regulate ciliary epithelial development by orchestrating the BMP, FGF and Notch signaling network.
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Keywords
lens development, ciliary epithelial development, Lhx2, FGF signaling, cataract