Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density.
Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density.
复制标题
神经管缺陷相关基因 Mthfd1l 的缺失会导致颅内间充质密度降低。
DOI：
10.1002/bdr2.1591
复制
发表时间：
2019
影响因子：
2.1
通讯作者：
Appling,DeanR
中科院分区：
文献类型：
--
作者：
Shin,Minhye;Vaughn,Amanda;Momb,Jessica;Appling,DeanR
围产期补充叶酸可降低神经管缺陷的发生率达70%，但叶酸支持神经管闭合过程中细胞过程的机制尚不清楚。线粒体10-甲酰基-四氢叶酸合成酶MTHFD 1 L催化甲酸盐的产生，从而为细胞质过程产生一个碳单元。缺失Mthfd 1 l导致胚胎死亡，发育迟缓，和神经管defects in mice.MethodsTo调查线粒体一碳代谢在颅神经管闭合过程中的作用，我们分析了细胞形态和功能在神经组织inMthfd 1 l敲除embryos.ResultsThe头部间充质表现出显着较低的细胞密度在Mthfd 1 lnullization胚胎相比，野生型胚胎在神经管闭合的过程中。细胞凋亡和神经嵴细胞的规格不受Mthfd 1 l的删除。从头部区域的Mthfd 1 l基因敲除胚胎切片表现出细胞增殖减少，但只有在完成神经管关闭。补充怀孕的母鼠与甲酸改善间充质密度和纠正细胞增殖在nullizygyzyembryos.ConclusionsDeletion of Mthfd 1 l的原因降低密度在颅间充质和这种缺陷是改善与甲酸补充。这项研究揭示了叶酸依赖性脑内产生的甲酸盐，头部间充质形成和神经管缺陷之间的机制联系。
BackgroundPericonceptional intake of supplemental folic acid can reduce the incidence of neural tube defects by as much as 70%, but the mechanisms by which folic acid supports cellular processes during neural tube closure are unknown. The mitochondrial 10‐formyl‐tetrahydrofolate synthetase MTHFD1L catalyzes production of formate, thus generating one‐carbon units for cytoplasmic processes. Deletion ofMthfd1lcauses embryonic lethality, developmental delay, and neural tube defects in mice.MethodsTo investigate the role of mitochondrial one‐carbon metabolism during cranial neural tube closure, we have analyzed cellular morphology and function in neural tissues inMthfd1lknockout embryos.ResultsThe head mesenchyme showed significantly lower cellular density inMthfd1lnullizygous embryos compared to wildtype embryos during the process of neural tube closure. Apoptosis and neural crest cell specification were not affected by deletion ofMthfd1l. Sections from the cranial region ofMthfd1lknockout embryos exhibited decreased cellular proliferation, but only after completion of neural tube closure. Supplementation of pregnant dams with formate improved mesenchymal density and corrected cell proliferation in the nullizygous embryos.ConclusionsDeletion ofMthfd1lcauses decreased density in the cranial mesenchyme and this defect is improved with formate supplementation. This study reveals a mechanistic link between folate‐dependent mitochondrially produced formate, head mesenchyme formation and neural tube defects.