Establishment of the neurogenic boundary of the mouse retina requires cooperation of SOX2 and WNT signaling.
Establishment of the neurogenic boundary of the mouse retina requires cooperation of SOX2 and WNT signaling.
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DOI：
10.1186/1749-8104-9-27
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发表时间：
2014-12-09
影响因子：
3.6
通讯作者：
Pevny LH
中科院分区：
文献类型：
--
作者：
Heavner WE;Andoniadou CL;Pevny LH
脊椎动物的眼睛发育依赖于 SOX2 表达的关键调节。 SOX2 突变的人类经常患有眼部缺陷，包括无眼症（无眼）和小眼症（小眼）。在小鼠中，视杯祖细胞中Sox2的缺失导致神经能力丧失和神经视网膜的细胞命运转变为非神经源性命运，特别是与睫状上皮祖细胞相关的命运的获得。视杯中稳定的 β-Catenin 的组成型表达也促进了这种命运，其中 WNT 通路上调。我们通过在小鼠中使用遗传方法来解决 SOX2 是否通过调节 WNT/β-Catenin 通路来协调视网膜的神经源性边界。在视杯中删除Sox2后，对WNT信号传导的反应扩大，与神经能力的丧失、神经视网膜的细胞命运转变为睫状上皮原基以及视杯祖细胞的细胞周期时间增加相关。 Ctnnb1的去除挽救了细胞命运的转变；然而，由于缺乏SOX2而导致的神经能力丧失和增殖缺陷并未得到克服。最后，中央 Sox2 缺陷的视杯祖细胞表现出 D 型细胞周期蛋白的 WNT 依赖性上调。我们提出 SOX2 在视网膜发育中具有两种不同的作用。我们的研究结果表明，SOX2 拮抗 WNT 通路以维持神经源性命运，相反，SOX2 以不依赖于 WNT 的方式调节视杯祖细胞的循环。鉴于作用于 SOX2 上游的 WNT 信号传导与胚胎干细胞衍生的视网膜祖细胞的致瘤性有关，我们的结果区分了 WNT 信号传导在早期视杯模式中的内源性作用，并支持 SOX2 在维持视网膜祖细胞增殖中的独立于 WNT 的作用。本文的在线版本 (doi:10.1186/1749-8104-9-27) 包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (doi:10.1186/1749-8104-9-27) contains supplementary material, which is available to authorized users.
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影响因子：
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