NIBS袭荣文续写Nature成果：干细胞分化机制

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来自北京生命科学学院的研究人员发表了题为“EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells”的文章，报道了果蝇肠上皮干细胞新的调节机制，并进一步证明了环形肌作为微环境维系干细胞的重要作用。/ L& Q# x( M/ @. G. \, U. o% G
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这是袭荣文博士继08年在Nature发表肠上皮干细胞分化机制文章后的又一研究新进展。其实验室博士后徐娜为该论文的第一作者。其他作者还有王思淇，谭丹，高亚威，林国南。此项研究为科技部863和北京市科委资助课题，在北京生命科学研究所完成。
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成体干细胞通常存在于一个特殊的微环境中得以长期维持。在果蝇的肠道中，已知Wnt/Wg 和JAK/STAT信号通路对肠上皮干细胞的维持和更新起重要作用。它们的信号因子在周围的环形肌中分泌，以旁分泌的形式调节干细胞的活性。因此环形肌构成了肠上皮干细胞的微环境。
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在这篇论文中，研究人员发现EGFR信号通路也对肠上皮干细胞的维持和更新起重要作用，并发现有三个配体参与。其中一个配体在环形肌中特异表达，另外两个在干细胞中表达。这样EGF 信号以旁分泌和自分泌两种形式维持着干细胞的自我更新。在干细胞中抑制EGFR会引起干细胞的活性下降和丢失。同时抑制三个信号通路可以加重这一表型，使干细胞在短期内完全丢失。另外，在三个信号通路中，一个通路的失活导致的干细胞活性下降可以被另外两个通路的过激活部分代偿。
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  s1 O8 M! |  A这些结果表明这三条信号通路共同起作用维持着肠上皮干细胞的自我更新。在人的肠道肿瘤中也常见EGFR通路的激活突变，因此该论文不但进一步揭示了肠上皮干细胞自我更新的分子机制，也将有助于理解肠道肿瘤等疾病的发生机制。4 u% M3 n# _5 m; l5 c9 O' p  U

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" f- \! ]3 t4 W3 ^$ Z; `- ~9 HEGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells.1 _  g* S* Y) H5 R, v$ h7 e; {
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Tissue-specific adult stem cells are commonly associated with local niche for their maintenance and function. In the adult Drosophila midgut, the surrounding visceral muscle maintains intestinal stem cells (ISCs) by stimulating Wingless (Wg) and JAK/STAT pathway activities, whereas cytokine production in mature enterocytes also induces ISC division and epithelial regeneration, especially in response to stress. Here we show that EGFR/Ras/ERK signaling is another important participant in promoting ISC maintenance and division in healthy intestine. The EGFR ligand Vein is specifically expressed in muscle cells and is important for ISC maintenance and proliferation. Two additional EGFR ligands, Spitz and Keren, function redundantly as possible autocrine signals to promote ISC maintenance and proliferation. Notably, over-activated EGFR signaling could partially replace Wg or JAK/STAT signaling for ISC maintenance and division, and vice versa. Moreover, although disrupting any single one of the three signaling pathways shows mild and progressive ISC loss over time, simultaneous disruption of them all leads to rapid and complete ISC elimination. Taken together, our data suggest that Drosophila midgut ISCs are maintained cooperatively by multiple signaling pathway activities and reinforce the notion that visceral muscle is a critical component of the ISC niche.( B* N1 x5 y  f2 a! {3 k) O* q3 P
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