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阐明Foxn1特异性调控胸腺T淋巴细胞发生而不影响造血干细胞的作用机制

胸腺是机体的重要免疫器官,由皮质和髓质两部分组成,主要包括胸腺上皮细胞和T淋巴细胞。胸腺病变将对机体免疫功能带来严重影响,使机体免疫自稳功能紊乱并伴发自身免疫性疾病。脊椎动物的胸腺在出生后比较活跃,但从青春期开始退化,是机体中最早退化的器官。但是,目前对于胸腺发育和T淋巴细胞产生的分子机制仍不清楚。

中科院动物研究所刘峰研究员领导的血液与心血管发育研究组以斑马鱼为模式生物,应用多种研究手段,发现胸腺发育重要基因Foxn1新的作用机制。通过敲低Foxn1的表达,发现其影响胸腺和T细胞发育。基因芯片实验证明,多个基因包括已知与胸腺发育相关的基因的表达受到了影响。基因功能研究发现,其中Mcm2和Cdca7在胸腺中的表达受到Foxn1调控,并且证明Mcm2是Foxn1的直接靶基因。功能恢复实验进一步证明了这一结论。研究最后发现,Foxn1和Mcm2敲低后胸腺发育的异常是由于细胞增殖缺陷导致的,这可能与Mcm2是DNA复制过程所必需的有关。

本研究首次发现Foxn1通过直接调控胸腺上皮细胞微环境的维持,介导胸腺上皮细胞和T淋巴细胞之间的相互作用,进而影响胸腺发育,为临床治疗胸腺和T淋巴细胞的早期退化提供了理论指导。

这项成果于12月3日在线发表于国际著名学术期刊PNAS (doi:10.1073/pnas.1217021110)。研究组助理研究员马东媛、博士研究生生王璐和王思峰为该论文共同第一作者。该研究得到了科技部、国家自然科学基金委和中国科学院的资助。

该研究组最近还应邀在Dev CompImmunol(doi:10.1016/j.dci.2011.12.013)发表了一篇综述文章,系统总结了脊椎动物中胸腺和T细胞发育的调控机制,尤其是信号通路和重要转录因子在这一过程中的作用。

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Foxn1 maintains thymic epithelial cells to support T-cell development via mcm2 in zebrafish

The thymus is mainly comprised of thymic epithelial cells (TECs), which form the unique thymic epithelial microenvironment essential for intrathymic T-cell development. Foxn1, a member of the forkhead transcription factor family, is required for establishing a functional thymic rudiment. However, the molecular mechanisms underlying the function of Foxn1 are still largely unclear. Here, we show that Foxn1 functions in thymus development through Mcm2 in the zebrafish. We demonstrate that, in foxn1 knockdown embryos, the thymic rudiment is reduced and T-cell development is impaired. Genome-wide expression profiling shows that a number of genes, including some known thymopoiesis genes, are dysregulated during the initiation of the thymus primordium and immigration of T-cell progenitors to the thymus. Functional and epistatic studies show that mcm2 and cdca7 are downstream of Foxn1, and mcm2 is a direct target gene of Foxn1 in TECs. Finally, we find that the thymus defects in foxn1 and mcm2 morphants might be attributed to reduced cell proliferation rather than apoptosis. Our results reveal that the foxn1-mcm2 axis plays a central role in the genetic regulatory network controlling thymus development in zebrafish.

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