Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor
Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor
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DOI：
10.1093/hmg/ddi098
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发表时间：
2005-04-15
影响因子：
3.5
通讯作者：
Nakafuku, M
中科院分区：
文献类型：
--
作者：
Azuma, N;Tadokoro, K;Nakafuku, M
Pax6基因在整个动物界的眼睛形态发生中起着重要作用。Pax6基因及其同源基因在果蝇和非洲爪蟾中的靶向表达可形成异位眼。因此，该基因至少在这些动物中是眼睛形态发生的主基因。在脊椎动物眼睛的早期发育中，Pax6是神经视网膜（NR）的多能祖细胞的指令所必需的。原始视网膜色素上皮（RPE）细胞能够在外源性干预下转换其表型并分化成NR，所述外源性干预包括用成纤维细胞生长因子（FGF）处理和手术去除内源性NR。然而，表型转换的分子基础仍然存在争议。在这里，我们表明，Pax6单独足以诱导异位NR从RPE细胞转分化，而不添加FGF或手术操作。Pax6介导的转分化甚至可以在发育的后期阶段被诱导。体内和体外研究均表明Pax6位于FGF信号的下游，突出了Pax6在NR转分化中的核心作用。我们的研究结果提供了近成熟RPE的视网膜形成潜力的证据，并提示新的治疗方法，以再生视力丧失患者的功能性NR。
The Pax6 gene plays an important role in eye morphogenesis throughout the animal kingdom. The Pax6 gene and its homologue could form ectopic eyes by targeted expression in Drosophila and Xenopus. Thus, this gene is a master gene for the eye morphogenesis at least in these animals. In the early development of the vertebrate eye, Pax6 is required for the instruction of multipotential progenitor cells of the neural retina (NR). Primitive retinal pigment epithelial (RPE) cells are able to switch their phenotype and differentiate into NR under exogenous intervention, including treatment with fibroblast growth factors (FGFs), and surgical removal of endogenous NR. However, the molecular basis of phenotypic switching is still controversial. Here, we show that Pax6 alone is sufficient to induce transdifferentiation of ectopic NR from RPE cells without addition of FGFs or surgical manipulation. Pax6-mediated transdifferentiation can be induced even at later stages of development. Both in vivo and in vitro studies show that the Pax6 lies downstream of FGF signaling, highlighting the central roles of Pax6 in NR transdifferentiation. Our results provide an evidence of retinogenic potential of nearly mature RPE and a cue for new therapeutic approaches to regenerate functional NR in patients with a visual loss.