Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis.
Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis.
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DOI：
10.1371/journal.pgen.1004491
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发表时间：
2014-07
期刊：
影响因子：
4.5
通讯作者：
Morris AC
中科院分区：
文献类型：
--
作者：
Pillai-Kastoori L;Wen W;Wilson SG;Strachan E;Lo-Castro A;Fichera M;Musumeci SA;Lehmann OJ;Morris AC
眼缺损是一种威胁视力的畸形，由眼的形态发生过程中脉络膜裂未能闭合引起，并且经常与其他异常相关，包括小眼球和白内障。尽管已知Hedgehog信号传导在脉络膜裂闭合中起关键作用，但对该途径的遗传调控仍然知之甚少。在这里，我们表明，转录因子Sox 11是必需的，以维持特定水平的刺猬信号在眼睛的发展。Sox 11缺陷斑马鱼胚胎显示延迟和异常的透镜形成，缺损，并在杆光感受器的特定减少，所有这些都可以通过刺猬途径抑制剂环巴胺治疗获救。我们进一步证明，在Sox 11缺陷斑马鱼的刺猬信号的升高是由shha转录的大幅增加引起的;事实上，抑制Shha表达拯救了sox 11 morphants的眼部表型。相反，过度表达sox 11诱导独眼畸形，这是一种与Sonic hedgehog水平降低一致的表型。我们筛选了79例小眼症、无眼症或缺损（MAC）患者的DNA样本，并在缺损患者中发现了两种新的杂合SOX 11变异体。与野生型人SOX 11 mRNA相比，mRNA含有任一变体未能拯救Sox 11缺陷斑马鱼的透镜和缺损表型，并且在荧光素酶报告基因测定中均表现出显著降低的反式激活能力。此外，从包含SOX 11基因座的节段性缺失中减少的基因剂量导致小眼症和相关的眼部表型。因此，我们的研究揭示了Sox 11在控制Hedgehog信号传导中的新作用，并表明SOX 11变体有助于儿童眼部疾病。眼缺损是一种由于发育异常而导致眼的一部分组织缺失的疾病。缺损也经常与其他异常有关，包括小眼症（异常小的眼睛）和白内障。虽然一些导致缺损的基因已经被确定，但在大多数情况下，潜在的遗传原因尚未确定。与缺损有关的一种途径是Hedgehog（Hh）信号通路。在这项研究中，我们利用了在斑马鱼中滴定基因表达水平的能力，首次证明了转录因子Sox 11是限制眼睛发育过程中Hedgehog（Hh）信号水平所必需的。我们发现，在没有Sox 11的情况下，Sonic Hedgehog（Shh）配体的水平大大升高，这破坏了视柄和视泡的正常模式，导致缺损。我们还提供了SOX 11剂量变化或突变导致人类缺损、小眼症和视杆细胞感光功能障碍的证据。因此，我们的工作在Sox 11和Hh信号传导之间建立了一种新的联系，并表明SOX 11的突变有助于儿童眼部疾病，如缺损。
Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders. Ocular coloboma is a condition in which tissue is missing from a portion of the eye due to its abnormal development. Coloboma is also frequently associated with additional anomalies, including microphthalmia (abnormally small eye) and cataracts. Although some of the genes that cause coloboma have been identified, in the majority of cases the underlying genetic cause has not been determined. One pathway that has been implicated in coloboma is the Hedgehog (Hh) signaling pathway. In this study, we have taken advantage of the ability to titrate levels of gene expression in zebrafish to demonstrate for the first time that the transcription factor Sox11 is required to limit levels of Hedgehog (Hh) signaling during ocular development. We show that in the absence of Sox11, levels of the Sonic Hedgehog (Shh) ligand are greatly elevated, which disrupts the proper patterning of the optic stalk and optic vesicle, resulting in coloboma. We also provide evidence that SOX11 dosage changes or mutations contribute to human coloboma, microphthalmia, and rod photoreceptor dysfunction. Thus, our work establishes a novel link between Sox11 and Hh signaling, and suggests that mutations in SOX11 contribute to pediatric eye disorders such as coloboma.
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