近日,，在《PLoS ONE》雜志上,，中國(guó)科學(xué)院昆明動(dòng)物研究所的研究人員發(fā)表了題為“Xenopus Reduced Folate Carrier Regulates Neural Crest Development Epigenetically”的研究論文，揭示了葉酸代謝途徑異常導(dǎo)致神經(jīng)嵴發(fā)育缺陷的分子機(jī)制,。
領(lǐng)導(dǎo)這一研究的是昆明動(dòng)物研究所的毛炳宇研究員,，其早年畢業(yè)于山東大學(xué)，后赴德國(guó)癌癥中心從事博士后研究,，于2004年起受聘成為昆明動(dòng)物研究所馬普青年科學(xué)家小組組長(zhǎng),。課題組主要研究方向是以非洲爪蟾為模型動(dòng)物，研究脊椎動(dòng)物神經(jīng)系統(tǒng)發(fā)育的分子機(jī)制,。
神經(jīng)嵴（neural crest,，NC）是脊椎動(dòng)物神經(jīng)系統(tǒng)發(fā)育過(guò)程中由多潛能細(xì)胞群體構(gòu)成的遷移性結(jié)構(gòu)，它最早形成于神經(jīng)板與表皮外胚層的交界處,，隨著神經(jīng)板卷曲及神經(jīng)管形成,，神經(jīng)嵴細(xì)胞逐漸下陷并向外遷移，最終分化為包括周?chē)窠?jīng)系統(tǒng)神經(jīng)元,、膠質(zhì)細(xì)胞,、骨,、軟骨、結(jié)締組織,、色素細(xì)胞及內(nèi)分泌細(xì)胞等在內(nèi)的多種組織細(xì)胞,。神經(jīng)嵴發(fā)育缺陷會(huì)導(dǎo)致一系列綜合征，包括顱面部畸形（唇腭裂）,，Waardenburg-Shah綜合征,，DiGeorge 綜合征, CHARGE 綜合征, 白化病，巨結(jié)腸等,。神經(jīng)嵴相關(guān)畸形的發(fā)病原因極為復(fù)雜,，是由一系列遺傳因素和環(huán)境（營(yíng)養(yǎng)）因素共同作用而引發(fā)的。孕期補(bǔ)充葉酸可以在一定程度上減少其發(fā)生率,，但葉酸的作用機(jī)理還不清楚,。
在這篇文章中，博士研究生李杰晶等人發(fā)現(xiàn)還原性葉酸載體（RFC）在非洲爪蛙神經(jīng)嵴發(fā)育中具有重要功能,。RFC在非洲爪蛙神經(jīng)嵴組織中特異性表達(dá),，干擾RFC的功能會(huì)抑制神經(jīng)嵴的發(fā)生，而過(guò)表達(dá)RFC或注射5-甲基四氫葉酸可以促進(jìn)神經(jīng)嵴的發(fā)生,。在動(dòng)物帽實(shí)驗(yàn)中,，抑制RFC的功能可顯著降低組織中組蛋白H3K4的甲基化水平，而注射葉酸則會(huì)提高組蛋白的甲基化水平,。在胚胎中過(guò)表達(dá)注射賴(lài)氨酸甲基轉(zhuǎn)移酶hMLL1在很大程度上挽救了RFC功能缺失所引起的神經(jīng)嵴發(fā)育畸形,，該研究表明葉酸代謝途徑可能通過(guò)表觀遺傳學(xué)修飾參與神經(jīng)嵴的發(fā)育和相關(guān)疾病的發(fā)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.
