SOX2 is a dose-dependent regulator of retinal neural progenitor competence
SOX2 is a dose-dependent regulator of retinal neural progenitor competence
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DOI：
10.1101/gad.1407906
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发表时间：
2006-05-01
影响因子：
10.5
通讯作者：
Pevny, LH
中科院分区：
文献类型：
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作者：
Taranova, OV;Magness, ST;Pevny, LH
大约 10% 的无眼症（无眼）或严重小眼症（小眼）患者因 SOX2（一种 SOXB1-HMG 盒转录因子）突变而表现出单倍体不足。然而，目前，人们对这些病症的分子或细胞机制知之甚少。在这里，我们通过在小鼠中产生一系列基因剂量等位基因的 Sox2 突变来直接评估眼睛发育过程中对 SOX2 的需求。 Sox2突变小鼠表现出一系列与人类综合症一致的眼部表型，并且这些表型的严重程度与神经视网膜祖细胞中发现的SOX2表达水平直接相关。 Sox2 条件性消融的视网膜祖细胞失去增殖和终末分化的能力。相比之下，在Sox2低效/缺失小鼠中，SOX2表达减少至正常值的40%以下，会因异常的神经祖细胞分化而导致不同程度的微血管畸形。此外，我们提供的遗传和分子证据表明，SOX2 活性以浓度依赖性方式在视网膜祖细胞中 NOTCH1 信号通路的调节中发挥关键作用。总的来说，这些结果表明，SOX2 剂量的精确调节对于视网膜祖细胞分化的时间和空间调节至关重要，并为了解 SOX2 的低效水平如何导致人类视网膜缺陷提供了细胞和分子模型。
Approximately 10% of humans with anophthalmia (absent eye) or severe microphthalmia (small eye) show haploid insufficiency due to mutations in SOX2, a SOXB1-HMG box transcription factor. However, at present, the molecular or cellular mechanisms responsible for these conditions are poorly understood. Here, we directly assessed the requirement for SOX2 during eye development by generating a gene-dosage allelic series of Sox2 mutations in the mouse. The Sox2 mutant mice display a range of eye phenotypes consistent with human syndromes and the severity of these phenotypes directly relates to the levels of SOX2 expression found in progenitor cells of the neural retina. Retinal progenitor cells with conditionally ablated Sox2 lose competence to both proliferate and terminally differentiate. In contrast, in Sox2 hypomorphic/null mice, a reduction of SOX2 expression to < 40% of normal causes variable microplithalmia as a result of aberrant neural progenitor differentiation. Furthermore, we provide genetic and molecular evidence that SOX2 activity, in a concentration-dependent manner, plays a key role in the regulation of the NOTCH1 signaling pathway in retinal progenitor cells. Collectively, these results show that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell differentiation and provide a cellular and molecular model for understanding how hypomorphic levels of SOX2 cause retinal defects in humans.