Establishment of the neurogenic boundary of the mouse retina requires cooperation of SOX2 and WNT signaling

Neural Development

Larysa H Pevny²  Cynthia L Andoniadou³  Whitney E Heavner¹ 

[1] Department of Biology, Stanford University, Stanford, CA 94305, USA;UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA;Division of Craniofacial Development and Stem Cell Biology, King’s College London, Guy’s Hospital, Floor 27 Tower Wing, London SE1 9RT, UK

关键词: SOX2;    Retina;    Proliferation;    Neural progenitor cells;    Eye development;    Cell cycle;    Canonical WNT signaling;    β-Catenin;   

Others  :  1146002
DOI  :  10.1186/1749-8104-9-27

 received in 2014-08-27, accepted in 2014-11-14,  发布年份 2014

【 摘 要 】

Background

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). 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.

Results

Upon 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.

Conclusion

We 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.

【 授权许可】

   
2014 Heavner et al.; licensee BioMed Central Ltd.

【 图 表 】

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