Abstract
BackgroundEye development in vertebrates relies on the critical regulation of SOX2 expression. Humans with mutations in SOX2 often suffer from eye defects including anophthalmia (no eye) and microphthalmia (small eye). In mice, deletion of Sox2 in optic cup progenitor cells results in loss of neural competence and cell fate conversion of the neural retina to a non-neurogenic fate, specifically the acquisition of fate associated with progenitors of the ciliary epithelium. This fate is also promoted with constitutive expression of stabilized β-Catenin in the optic cup, where the WNT pathway is up-regulated. We addressed whether SOX2 co-ordinates the neurogenic boundary of the retina through modulating the WNT/β-Catenin pathway by using a genetic approach in the mouse.ResultsUpon deletion of Sox2 in the optic cup, response to WNT signaling was expanded, correlating with loss of neural competence, cell fate conversion of the neural retina to ciliary epithelium primordium and, in addition, increased cell cycle time of optic cup progenitors. Removal of Ctnnb1 rescued the cell fate conversion; however, the loss of neural competence and the proliferation defect resulting from lack of SOX2 were not overcome. Lastly, central Sox2-deficient optic cup progenitor cells exhibited WNT-independent up-regulation of D-type Cyclins.ConclusionWe propose two distinct roles for SOX2 in the developing retina. Our findings suggest that SOX2 antagonizes the WNT pathway to maintain a neurogenic fate and, in contrast, regulates cycling of optic cup progenitors in a WNT-independent manner. Given that WNT signaling acting upstream of SOX2 has been implicated in the tumorigenicity of embryonic stem cell-derived retinal progenitor cells, our results distinguish the endogenous role of WNT signaling in early optic cup patterning and support a WNT-independent role for SOX2 in maintaining retinal progenitor cell proliferation.Electronic supplementary materialThe online version of this article (doi:10.1186/1749-8104-9-27) contains supplementary material, which is available to authorized users.
Highlights
Eye development in vertebrates relies on the critical regulation of SOX2 expression
We present whole-genome expression arrays comparing wild-type and Sox2-mutant optic cup (OC) demonstrating the deregulation of the WNT pathway and serving as a resource for identifying genes involved in ciliary epithelium (CE) fate and function, with direct relevance to understanding the pathogenesis of diseases associated with the anterior segment
Canonical WNT signaling is ectopically activated in Sox2-mutant optic cups Ablation of Sox2 in the mouse OC from E10.5 leads to eventual loss of neural retina (NR) fate and expansion of the nonneurogenic CE [5]
Summary
Eye development in vertebrates relies on the critical regulation of SOX2 expression. Humans with mutations in SOX2 often suffer from eye defects including anophthalmia (no eye) and microphthalmia (small eye). Deletion of Sox in optic cup progenitor cells results in loss of neural competence and cell fate conversion of the neural retina to a non-neurogenic fate, the acquisition of fate associated with progenitors of the ciliary epithelium. This fate is promoted with constitutive expression of stabilized β-Catenin in the optic cup, where the WNT pathway is up-regulated. Stabilized expression of Ctnnb in mouse OCPCs induced ectopic expression of CE-specific genes [8] These ectopic CE-like cells did not express Pax or Chx, two well-known transcriptional regulators of CE fate, suggesting that there was only a partial transformation of NR-to-CE upon activation of Ctnnb
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