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Abstract：
The optic vesicle comprises a pool of bi-potential progenitor cells from which the retinal pigment epithelium (RPE) and neural retina fates segregate during ocular morphogenesis. Several transcription factors and signaling pathways have been shown to be important for RPE maintenance and differentiation, but an understanding of the initial fate specification and determination of this ocular cell type is lacking. We show that Yap/Taz-Tead activity is necessary and sufficient for optic vesicle progenitors to adopt RPE identity in zebrafish. A Tead-responsive transgene is expressed within the domain of the optic cup from which RPE arises, and Yap immunoreactivity localizes to the nuclei of prospective RPE cells. yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma. Loss of RPE in yap mutants is exacerbated in combination with taz (wwtr1) mutant alleles such that, when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE. The mechanism of Yap-dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor. In contrast to loss of Yap and Taz, overexpression of either protein within optic vesicle progenitors leads to ectopic pigmentation in a dosage-dependent manner. Overall, this study identifies Yap and Taz as key early regulators of RPE genesis and provides a mechanistic framework for understanding the congenital ocular defects of Sveinsson\'s chorioretinal atrophy and congenital retinal coloboma.
摘要：
光学囊泡包括双电位祖细胞池,在眼部形态发生期间,视网膜色素上皮(RPE)和神经视网膜命运从其分离。一些转录因子和信号通路已被证明对RPE的维持和分化很重要。但是缺乏对这种眼细胞类型的初始命运规范和确定的理解。我们表明，Yap/Taz-Tead活性对于斑马鱼中的视泡祖细胞采用RPE身份是必要且足够的。Tead反应性转基因在产生RPE的视杯结构域内表达，Yap免疫反应性位于预期的RPE细胞的细胞核。yap(yapl)突变体缺乏RPE细胞的子集和/或表现出结肠瘤。与taz（wwtr1）突变等位基因组合会加剧yap突变体中RPE的丢失，当Yap和Taz都缺席时,视神经囊泡祖细胞完全丧失形成RPE的能力。Yap依赖性RPE细胞类型确定的机制依赖于Yap的核定位和与Tead辅因子的相互作用。与失去Yap和Taz相反，视泡祖细胞中任何一种蛋白质的过表达均以剂量依赖性方式导致异位色素沉着。总的来说,本研究将Yap和Taz确定为RPE发生的关键早期调节因子，并为了解Sveinsson脉络膜视网膜萎缩和先天性视网膜缺损的先天性眼部缺陷提供了一个机制框架。
