The Forkhead Box C1 (FOXC1) gene encodes a forkhead/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by FOXC1 remain largely unknown. There are two conserved orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. To further examine the role of FOXC1 in vertebrates, we generated foxc1a and foxc1b single knockout zebrafish lines and bred them to obtain various allelic combinations. Three genotypes demonstrated visible phenotypes: foxc1a^−/− single homozygous and foxc1^−/− double knockout homozygous embryos presented with similar characteristics comprised of severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye; additionally, fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a^+/−;foxc1b^−/−) demonstrated craniofacial defects, heart anomalies and scoliosis. All other single and combined genotypes appeared normal. Analysis of foxc1 expression detected a significant increase in foxc1a levels in homozygous and heterozygous mutant eyes, suggesting a mechanism for foxc1a upregulation when its function is compromised; interestingly, the expression of another ARS-associated gene, pitx2, was responsive to the estimated level of wild-type Foxc1a, indicating a possible role for this protein in the regulation of pitx2 expression. Altogether, our results support a conserved role for foxc1 in the formation of many organs, consistent with the features observed in human patients, and highlight the importance of correct FOXC1/foxc1 dosage for vertebrate development.

中文翻译：

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斑马鱼中 foxc1 基因的中断导致剂量依赖性表型与 Axenfeld-Rieger 综合征重叠。

Forkhead Box C1 ( FOXC1 ) 基因编码涉及胚胎发育的叉头/翼状螺旋转录因子。该基因的突变导致眼前节发育不全，最常见的是 Axenfeld-Rieger 综合征 (ARS)，通常伴有其他全身特征。FOXC1调控的发育机制和途径在很大程度上仍然未知。斑马鱼中有两个保守的FOXC1直向同源物，foxc1a和foxc1b。为了进一步研究FOXC1在脊椎动物中的作用，我们生成了foxc1a和foxc1b单个敲除斑马鱼系并培育它们以获得各种等位基因组合。三种基因型显示出可见的表型：foxc1a ^-/-单纯合子和foxc1 ^-/-双敲除纯合子胚胎具有相似的特征，包括严重的整体血管缺陷和早期致死率，以及小眼症、眼周水肿和前房缺失。眼睛; 此外，foxc1a杂合缺失与foxc1b纯合性结合的鱼（foxc1a ^+/- ; foxc1b ^-/-) 表现出颅面缺陷、心脏异常和脊柱侧弯。所有其他单一和组合基因型都显示正常。对foxc1表达的分析检测到在纯合子和杂合子突变眼中foxc1a水平显着增加，表明foxc1a功能受损时上调的机制；有趣的是，另一种 ARS 相关基因pitx2的表达对野生型 Foxc1a 的估计水平有反应，表明该蛋白质在调节pitx2表达中可能发挥作用。总而言之，我们的结果支持foxc1的保守作用在许多器官的形成中，与在人类患者中观察到的特征一致，并强调了正确的FOXC1/foxc1剂量对脊椎动物发育的重要性。