Tu Hung-Chi, Lee Gang-Hui, Hsiao Tsun-Hsien, Kao Tseng-Ting, Wang Tzu-Ya, Tsai Jen-Ning, Fu Tzu-Fun
The Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan.
Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, College of Medicine, Tainan, Taiwan.
PLoS One. 2017 Nov 27;12(11):e0188585. doi: 10.1371/journal.pone.0188585. eCollection 2017.
Folate (vitamin B9) is an essential nutrient required for cell survival, proliferation, differentiation and therefore embryogenesis. Folate deficiency has been associated with many diseases, including congenital heart diseases and megaloblastic anemia, yet the mechanisms underlying these remains elusive. Here, we examine the impact of folate deficiency on the development of the circulation system using a zebrafish transgenic line which displays inducible folate deficiency. Impaired hematopoiesis includes decreased hemoglobin levels, decreased erythrocyte number, increased erythrocyte size and aberrant c-myb expression pattern were observed in folate deficient embryos. Cardiac defects, including smaller chamber size, aberrant cardiac function and cmlc2 expression pattern, were also apparent in folate deficient embryos. Characterization of intracellular folate content in folate deficiency revealed a differential fluctuation among the different folate derivatives that carry a single carbon group at different oxidation levels. Rescue attempts by folic acid and nucleotides resulted in differential responses among affected tissues, suggesting that different pathomechanisms are involved in folate deficiency-induced anomalies in a tissue-specific manner. The results of the current study provide an explanation for the inconsistent outcome observed clinically in patients suffering from folate deficiency and/or receiving folate supplementation. This study also supports the use of this model for further research on the defective cardiogenesis and hematopoiesis caused by folate deficiency.
叶酸（维生素B9）是细胞存活、增殖、分化以及胚胎发育所必需的一种营养物质。叶酸缺乏与多种疾病相关，包括先天性心脏病和巨幼细胞贫血，但其潜在机制仍不清楚。在此，我们利用一种可诱导叶酸缺乏的斑马鱼转基因品系，研究叶酸缺乏对循环系统发育的影响。在叶酸缺乏的胚胎中观察到造血功能受损，包括血红蛋白水平降低、红细胞数量减少、红细胞大小增加以及c-myb表达模式异常。心脏缺陷，包括腔室尺寸变小、心脏功能异常以及cmlc2表达模式异常，在叶酸缺乏的胚胎中也很明显。对叶酸缺乏时细胞内叶酸含量的表征揭示了不同叶酸衍生物之间的差异波动，这些衍生物在不同氧化水平携带单个碳基团。用叶酸和核苷酸进行的挽救尝试在受影响的组织中产生了不同的反应，这表明不同的病理机制以组织特异性方式参与了叶酸缺乏诱导的异常。本研究结果为临床上叶酸缺乏患者和/或接受叶酸补充治疗的患者所观察到的不一致结果提供了解释。本研究还支持使用该模型进一步研究叶酸缺乏引起的心脏发生和造血缺陷。
