Neuroretina specification in mouse embryos requires S1x3-mediated suppression of Wnt8b in the anterior neural plate
Neuroretina specification in mouse embryos requires S1x3-mediated suppression of Wnt8b in the anterior neural plate
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DOI：
10.1172/jci43219
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发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Oliver, Guillermo
中科院分区：
文献类型：
--
作者：
Liu, Wei;Lagutin, Oleg;Oliver, Guillermo
视网膜变性导致人类视力受损和失明。如果有一天我们要利用基于干细胞的细胞替代疗法来治疗这些疾病，那么我们必须更好地了解正常的视网膜发育。目前，在脊椎动物眼睛发育过程中调节神经视网膜特化的基因和机制仍然未知。在这里，我们确定了sine oculis相关的同源异型盒3（Six3）在小鼠的这一过程中起着至关重要的作用。在Six3条件突变的小鼠胚胎，规格的神经视网膜被废除，但视网膜色素上皮细胞是正常的。Six3的条件性缺失不影响视泡的初始发育，但确实阻止了随后的神经视网膜特异性。Wnt8b表达的异位吻侧扩张是Six3缺失的主要反应，也是神经视网膜特异性缺乏的主要原因，因为转基因胚胎中的异位Wnt8b表达足以抑制神经视网膜特异性。使用染色质免疫沉淀试验，我们确定了Six3响应元件在Wnt8b基因座，并证明Six3直接抑制Wnt8b在体内的表达。我们的研究结果提供了一个分子框架的程序，导致神经视网膜分化，并可能是相关的新的战略，旨在表征和最终治疗不同的眼睛形成异常的发展。
Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.