中科院動(dòng)物研究所劉峰研究員領(lǐng)導(dǎo)的血液與心血管發(fā)育研究組以斑馬魚(yú)和人臍帶血為研究模型,，應(yīng)用遺傳學(xué),、細(xì)胞生物學(xué)和分子生物學(xué)等多種研究手段，發(fā)現(xiàn)ETS家族轉(zhuǎn)錄因子Fev在造血干細(xì)胞發(fā)育中起到重要作用,。在斑馬魚(yú)中敲低Fev導(dǎo)致造血干細(xì)胞及T細(xì)胞數(shù)量明顯減少,。應(yīng)用TALEN技術(shù)得到的該基因遺傳突變體也證實(shí)這一發(fā)現(xiàn)?；蚬δ苎芯繉?shí)驗(yàn)發(fā)現(xiàn),，F(xiàn)ev可以直接調(diào)控ERK信號(hào)通路，并且證實(shí)erk2是Fev的一個(gè)直接靶基因,。移植實(shí)驗(yàn)證明,，F(xiàn)ev通過(guò)細(xì)胞自主性方式影響HSC的發(fā)育。重要的是,，F(xiàn)ev也在人類造血干/祖細(xì)胞中特異性表達(dá)并影響其自我更新和維持,，證明該基因在高等哺乳動(dòng)物造血系統(tǒng)中的保守作用。
本研究從分子水平系統(tǒng)分析轉(zhuǎn)錄因子fev基因的表達(dá)調(diào)控機(jī)制,，建立其與相關(guān)造血干細(xì)胞主控基因及信號(hào)通路之間調(diào)控的關(guān)系,，有助于豐富我們對(duì)造血干細(xì)胞發(fā)育和分化調(diào)控機(jī)制的認(rèn)識(shí),，并為體外重編程產(chǎn)生和擴(kuò)增可移植、有功能的造血干細(xì)胞提供了理論基礎(chǔ),。
該項(xiàng)研究成果于7月18日以封面文章發(fā)表于國(guó)際學(xué)術(shù)期刊BLOOD (Blood 122(3):367-375 ),。博士研究生王璐為第一作者、上海交通大學(xué)醫(yī)學(xué)院博士研究生劉天會(huì)和北京大學(xué)生命科學(xué)學(xué)院徐琳杰為本論文共同第一作者,；動(dòng)物所劉峰研究員和上海交通大學(xué)醫(yī)學(xué)院洪登禮研究員為共同通訊作者,。
該研究得到科技部、國(guó)家自然科學(xué)基金委和中國(guó)科學(xué)院干細(xì)胞先導(dǎo)專項(xiàng)的支持,。（生物谷 Bioon.com）
生物谷推薦的英文摘要
Blood doi: 10.1182/blood-2012-10-462655
Fev regulates hematopoietic stem cell development via ERK signaling
Lu Wang1, Tianhui Liu2, Linjie Xu3, Ya Gao1, Yonglong Wei1, Caiwen Duan2, Guo-Qiang Chen2, Shuo Lin4, Roger Patient5, Bo Zhang3, Dengli Hong2, and Feng Liu1
Reprogramming of somatic cells to desired cell types holds great promise in regenerative medicine. However, production of transplantable hematopoietic stem cells (HSCs) in vitro by defined factors has not yet been achieved. Therefore, it is critical to fully understand the molecular mechanisms of HSC development in vivo. Here, we show that Fev, an ETS transcription factor, is a pivotal regulator of HSC development in vertebrates. In fev-deficient zebrafish embryos, the first definitive HSC population was compromised and fewer T cells were found in the thymus. Genetic and chemical analyses support a mechanism whereby Fev regulates HSC through direct regulation of ERK signaling. Blastula transplant assay demonstrates that Fev regulation of HSC development is cell autonomous. Experiments performed with purified cord blood show that fev is expressed and functions in primitive HSCs in humans, indicating its conserved role in higher vertebrates. Our data indicate that Fev-ERK signaling is essential for hemogenic endothelium-based HSC development.
