The Transcription Factor Foxg1 Promotes Optic Fissure Closure in the Mouse by Suppressing Wnt8b in the Nasal Optic Stalk.
The Transcription Factor Foxg1 Promotes Optic Fissure Closure in the Mouse by Suppressing Wnt8b in the Nasal Optic Stalk.
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DOI：
10.1523/jneurosci.0286-17.2017
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发表时间：
2017-08-16
期刊：
影响因子：
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通讯作者：
Fotaki V
中科院分区：
文献类型：
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作者：
Smith R;Huang YT;Tian T;Vojtasova D;Mesalles-Naranjo O;Pollard SM;Pratt T;Price DJ;Fotaki V
在脊椎动物眼睛形态发生期间，在其下部形成短暂的裂隙，称为视裂。这将逐渐关闭，产生健康的球形视杯。视神经裂不能闭合会引起一种称为缺损的眼部疾病。在这个发育过程中，Foxg 1在视神经上皮中表达，在鼻视柄中表达水平最高。Foxg 1 −/−突变小鼠有小眼，腹部有一个大的缺损。我们发现Wnt 8b在Foxg 1 −/−视柄中表达上调，并假设与端脑发育中观察到的相似，Foxg 1通过Wnt 8b的转录抑制指导视神经上皮的发育。为了验证这一点，我们产生了Foxg 1 −/−; Wnt 8b −/−双突变体，发现这些胚胎中视杯和视杆的形态以及视裂的闭合基本上得到了拯救。这种拯救与视神经裂前端Pax 2表达的恢复相关。此外，虽然我们没有发现证据表明在拯救中增殖发生了改变，但我们观察到Foxg 1 −/−; Wnt 8b −/−双突变体中凋亡细胞密度比Foxg 1 −/−单突变体显著增加。视杯和视柄中Wnt/β-catenin靶分子的上调可能是Foxg 1 −/−突变体中分子和形态缺陷的基础。我们的研究结果表明，适当的视裂关闭依赖于Wnt 8b抑制Foxg 1在鼻视柄，以保持平衡的细胞凋亡和Pax 2表达的鼻和颞边缘的裂缝。重要性声明缺损是一种可能导致视力丧失的眼部疾病，占儿童失明的10%。它是由视神经裂（OF）的封闭错误引起的，视神经裂是眼睛底部的一个短暂结构。在这里，我们研究了Foxg 1 −/−突变小鼠的缺损表型。我们确定上调表达的Wnt 8b在FOXG 1 −/−突变体的视柄前OF关闭启动。Foxg1−/−; Wnt 8b −/−双突变体显示出对Foxg 1 −/−缺损表型的实质性拯救，这与Foxg 1 −/−突变体的分子和细胞缺陷的拯救相关。我们的研究结果揭示了Foxg 1在促进OF闭合中的新作用，为缺损形成的分子和细胞机制提供了更多的知识。
During vertebrate eye morphogenesis, a transient fissure forms at its inferior part, known as the optic fissure. This will gradually close, giving rise to a healthy, spherical optic cup. Failure of the optic fissure to close gives rise to an ocular disorder known as coloboma. During this developmental process, Foxg1 is expressed in the optic neuroepithelium, with highest levels of expression in the nasal optic stalk. Foxg1−/− mutant mice have microphthalmic eyes with a large ventral coloboma. We found Wnt8b expression upregulated in the Foxg1−/− optic stalk and hypothesized that, similar to what is observed in telencephalic development, Foxg1 directs development of the optic neuroepithelium through transcriptional suppression of Wnt8b. To test this, we generated Foxg1−/−;Wnt8b−/− double mutants of either sex and found that the morphology of the optic cup and stalk and the closure of the optic fissure were substantially rescued in these embryos. This rescue correlates with restored Pax2 expression in the anterior tip of the optic fissure. In addition, although we do not find evidence implicating altered proliferation in the rescue, we observe a significant increase in apoptotic cell density in Foxg1−/−;Wnt8b−/− double mutants compared with the Foxg1−/− single mutant. Upregulation of Wnt/β-catenin target molecules in the optic cup and stalk may underlie the molecular and morphological defects in the Foxg1−/− mutant. Our results show that proper optic fissure closure relies on Wnt8b suppression by Foxg1 in the nasal optic stalk to maintain balanced apoptosis and Pax2 expression in the nasal and temporal edges of the fissure. SIGNIFICANCE STATEMENT Coloboma is an ocular disorder that may result in a loss of visual acuity and accounts for ∼10% of childhood blindness. It results from errors in the sealing of the optic fissure (OF), a transient structure at the bottom of the eye. Here, we investigate the colobomatous phenotype of the Foxg1−/− mutant mouse. We identify upregulated expression of Wnt8b in the optic stalk of Foxg1−/− mutants before OF closure initiates. Foxg1−/−;Wnt8b−/− double mutants show a substantial rescue of the Foxg1−/− coloboma phenotype, which correlates with a rescue in molecular and cellular defects of Foxg1−/− mutants. Our results unravel a new role of Foxg1 in promoting OF closure providing additional knowledge about the molecules and cellular mechanisms underlying coloboma formation.