近日,在《PLoS ONE》杂志上,中国科学院昆明动物研究所的研究人员发表了题为“Xenopus Reduced Folate Carrier Regulates Neural Crest Development Epigenetically”的研究论文,揭示了叶酸代谢途径异常导致神经嵴发育缺陷的分子机制。
领导这一研究的是昆明动物研究所的毛炳宇研究员,其早年毕业于山东大学,后赴德国癌症中心从事博士后研究,于2004年起受聘成为昆明动物研究所马普青年科学家小组组长。课题组主要研究方向是以非洲爪蟾为模型动物,研究脊椎动物神经系统发育的分子机制。
神经嵴(neural crest,NC)是脊椎动物神经系统发育过程中由多潜能细胞群体构成的迁移性结构,它最早形成于神经板与表皮外胚层的交界处,随着神经板卷曲及神经管形成,神经嵴细胞逐渐下陷并向外迁移,最终分化为包括周围神经系统神经元、胶质细胞、骨、软骨、结缔组织、色素细胞及内分泌细胞等在内的多种组织细胞。神经嵴发育缺陷会导致一系列综合征,包括颅面部畸形(唇腭裂),Waardenburg-Shah综合征,DiGeorge 综合征, CHARGE 综合征, 白化病,巨结肠等。神经嵴相关畸形的发病原因极为复杂,是由一系列遗传因素和环境(营养)因素共同作用而引发的。孕期补充叶酸可以在一定程度上减少其发生率,但叶酸的作用机理还不清楚。
在这篇文章中,博士研究生李杰晶等人发现还原性叶酸载体(RFC)在非洲爪蛙神经嵴发育中具有重要功能。RFC在非洲爪蛙神经嵴组织中特异性表达,干扰RFC的功能会抑制神经嵴的发生,而过表达RFC或注射5-甲基四氢叶酸可以促进神经嵴的发生。在动物帽实验中,抑制RFC的功能可显著降低组织中组蛋白H3K4的甲基化水平,而注射叶酸则会提高组蛋白的甲基化水平。在胚胎中过表达注射赖氨酸甲基转移酶hMLL1在很大程度上挽救了RFC功能缺失所引起的神经嵴发育畸形,该研究表明叶酸代谢途径可能通过表观遗传学修饰参与神经嵴的发育和相关疾病的发生。(生物谷Bioon.com)
doi:10.1371/journal.pone.0027198
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Xenopus Reduced Folate Carrier Regulates Neural Crest Development Epigenetically
Jiejing Li1,2, Yu Shi1¤, Jian Sun1,2, Yanfeng Zhang1,2, Bingyu Mao1*
Folic acid deficiency during pregnancy causes birth neurocristopathic malformations resulting from aberrant development of neural crest cells. The Reduced folate carrier (RFC) is a membrane-bound receptor for facilitating transfer of reduced folate into the cells. RFC knockout mice are embryonic lethal and develop multiple malformations, including neurocristopathies. Here we show that XRFC is specifically expressed in neural crest tissues in Xenopus embryos and knockdown of XRFC by specific morpholino results in severe neurocristopathies. Inhibition of RFC blocked the expression of a series of neural crest marker genes while overexpression of RFC or injection of 5-methyltetrahydrofolate expanded the neural crest territories. In animal cap assays, knockdown of RFC dramatically reduced the mono- and trimethyl-Histone3-K4 levels and co-injection of the lysine methyltransferase hMLL1 largely rescued the XRFC morpholino phenotype. Our data revealed that the RFC mediated folate metabolic pathway likely potentiates neural crest gene expression through epigenetic modifications.