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Whitney E. Heavner, Danielle Matsushima, Larysa H. Pevny; SOX2 Regulates Neural Retina Development Through Antagonism of Canonical Wnt Signaling. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1316.
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© ARVO (1962-2015); The Authors (2016-present)
Around 10% of human individuals with anophthalmia (no eye) or severe microphthalmia (small eye) carry a mutation in the gene encoding the HMG-box transcription factor SOX2. Our lab has previously shown that ablation of SOX2 in mouse optic cup progenitor cells results in cell fate conversion from neurogenic neural retina (NR) to non-neurogenic ciliary epithelium (CE) (Matsushima et al. 2011). These data suggest that SOX2 is a decisive factor of neural competence in the developing retina. Recent work in the Pevny lab has focused on determining how SOX2 maintains the competence of retinal progenitor cells to become neurons. Retinal progenitor cells provide an especially useful model for determining SOX2’s role in neurogenesis given that these cells retain the ability to become non-neurogenic CE if SOX2 is lost. It has been demonstrated that expression of stabilized β-catenin, the major transcriptional mediator of canonical Wnt signaling, in retinal progenitor cells induces expression of CE-specific genes (Liu et al. 2007). The current study examines the hypothesis that SOX2 maintains neural competence in the developing retina in part by antagonizing canonical Wnt signaling.
Genetic epistasis analysis was used to determine the relationship between SOX2 and β-catenin in the developing optic cup. Cell cycle kinetics was analyzed using flow cytometry, global gene expression analysis and double labeling with thymidine analogs.
Deletion of Sox2 in retinal progenitor cells resulted in expanded Wnt signaling into the central optic cup/prospective neural retina. At embryonic day (E) 16.5, the Wnt target gene CyclinD1 was upregulated in central Sox2-mutant cells but not in more peripheral Sox2-mutant cells. The increase in CyclinD1 was associated with a decrease p27kip1. The pattern of CyclinD1 upregulation was opposite to the graded decrease in cell cycle rate. Thus, more peripheral Sox2-mutant cells exhibited longer cell cycle times and down-regulated CyclinD1 expression. By postnatal day 0, Sox2-mutant cells had exited the cell cycle. Deletion of both Sox2 and β-catenin in retinal progenitor cells partially rescued the Sox2-mutant phenotype. However, CyclinD1 remained upregulated in double-mutant cells at E16.5.
Results from these studies suggest that SOX2 maintains neural retinal identity in part by antagonizing canonical Wnt signaling upstream of β-catenin. Moreover, SOX2 may regulate retinal progenitor cell proliferation through control of G1 cell cycle components. SOX2’s role in canonical Wnt signaling can be separated from its role in progenitor cell proliferation given that CyclinD1 remains upregulated in Sox2-mutant cells that lack β-catenin.
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