Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation
Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation
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DOI：
10.1016/j.celrep.2018.10.106
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发表时间：
2018-11-27
期刊：
影响因子：
8.8
通讯作者：
Liu, Wei
中科院分区：
文献类型：
--
作者：
Diacou, Raven;Zhao, Yilin;Liu, Wei
多能神经视网膜祖细胞的基因调控部分被理解。通过表征Six 3和Six 6双敲除视网膜（DKO），我们证明Six 3和Six 6是维持多能神经视网膜祖细胞所共同需要的。在Six 3无效或Six 6无效中均未发现DKO的表型。在远周边，睫状缘（CM）标记物Otx 1和Cdon连同Wnt 3a和Fzd 1异位上调，而神经视网膜祖细胞标记物Sox 2，Notch 1和Otx 2不存在或减少。在中周边，多谱系分化是有缺陷的。Six 3和Six 6共同调控的基因组与WNT 3A、CTNNB 1、POU 4F 2或SOX 2调控的基因网络显著重叠。通过Wnt-3a或GS 3 K β抑制剂刺激Wnt/β-连环蛋白信号传导促进了CM祖细胞，但以眼杯周围的神经视网膜特性为代价。因此，Six 3和Six 6一起直接或间接抑制Wnt/β-连环蛋白信号传导，但促进视网膜生成因子以维持多能神经视网膜祖细胞。
Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing Six3 and Six6 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitors. Phenotypes in DKOs were not found in either Six3 nulls or Six6 nulls. At the far periphery, ciliary margin (CM) markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically upregulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. At the mid periphery, multi-lineage differentiation was defective. The gene set jointly regulated by Six3 and Six6 significantly overlapped with the gene networks regulated by WNT3A, CTNNB1, POU4F2, or SOX2. Stimulation of Wnt/beta-catenin signaling by either Wnt-3a or a GS3K beta inhibitor promoted CM progenitors at the cost of neuroretinal identity at the periphery of eyecups. Therefore, Six3 and Six6 together directly or indirectly suppress Wnt/beta-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors.