Three RNA binding proteins form a complex to promote differentiation of germline stem cell lineage in Drosophila.
Three RNA binding proteins form a complex to promote differentiation of germline stem cell lineage in Drosophila.
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三种 RNA 结合蛋白形成复合物，促进果蝇生殖干细胞谱系的分化。
DOI：
10.1371/journal.pgen.1004797
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发表时间：
2014-11
期刊：
影响因子：
4.5
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Chen D;Wu C;Zhao S;Geng Q;Gao Y;Li X;Zhang Y;Wang Z
在再生组织中，保护干细胞免受可能由频繁细胞分裂引起的遗传畸变的策略之一是在进一步分化之前瞬时扩增干细胞子代。然而，未能退出过境扩增可能会导致过度生长，这种调节的分子机制仍然模糊。在果蝇诱变筛选的因素参与生殖系干细胞（GSC）谱系的调节，我们分离出的基因CG 32364，它编码一个假定的RNA结合蛋白（RBP）的突变，并被指定为肿瘤睾丸（图特）。在tut突变体中，精原细胞无法分化并过度扩增，其表型与mei-P26突变体相似。Mei-P26是GSC谱系分化所需的TRIM-NHL肿瘤抑制同源物。我们发现Tut优先结合mei-P26 3′UTR的长异构体，并且对于mei-P26报告基因的翻译抑制是必需的。BAM和Bgcn都是RBP，也已显示抑制mei-P26表达。我们的遗传分析表明，tut，bam，或bgcn需要抑制mei-P26和促进GSC的分化。在生物化学上，我们证明了Tut，BAM和Bgcn可以形成一个物理复合物，其中BAM在其N-末端上持有Tut，在其C-末端上持有Bgcn。我们在体内和体外的证据表明，Tut与Bam，Bgcn准确地协调果蝇生殖干细胞系的增殖和分化。在再生组织中，干细胞谱系的连续分化在每个分化阶段都得到良好的控制和协调，并伴有适当的细胞增殖。控制机制的破坏可导致肿瘤生长或组织变性。果蝇精子发生的生殖系干细胞谱系为阐明调节增殖和分化的遗传网络提供了理想的研究模型。在遗传筛选中，我们发现了一个雄性不育突变体，其生殖细胞分化不足和过度增殖。负责基因编码RNA结合蛋白，其靶点属于肿瘤抑制基因家族。我们证明，这和其他两个RNA结合蛋白形成一个物理和功能单位，以确保生殖系干细胞谱系的正确分化和准确增殖。
In regenerative tissues, one of the strategies to protect stem cells from genetic aberrations, potentially caused by frequent cell division, is to transiently expand the stem cell daughters before further differentiation. However, failure to exit the transit amplification may lead to overgrowth, and the molecular mechanism governing this regulation remains vague. In a Drosophila mutagenesis screen for factors involved in the regulation of germline stem cell (GSC) lineage, we isolated a mutation in the gene CG32364, which encodes a putative RNA-binding protein (RBP) and is designated as tumorous testis (tut). In tut mutant, spermatogonia fail to differentiate and over-amplify, a phenotype similar to that in mei-P26 mutant. Mei-P26 is a TRIM-NHL tumor suppressor homolog required for the differentiation of GSC lineage. We found that Tut binds preferentially a long isoform of mei-P26 3′UTR, and is essential for the translational repression of mei-P26 reporter. Bam and Bgcn are both RBPs that have also been shown to repress mei-P26 expression. Our genetic analyses indicate that tut, bam, or bgcn is required to repress mei-P26 and to promote the differentiation of GSCs. Biochemically, we demonstrate that Tut, Bam, and Bgcn can form a physical complex in which Bam holds Tut on its N-terminus and Bgcn on its C-terminus. Our in vivo and in vitro evidence illustrate that Tut acts with Bam, Bgcn to accurately coordinate proliferation and differentiation in Drosophila germline stem cell lineage. In regenerative tissues, the successive differentiation of stem cell lineage is well controlled and coordinated with proper cell proliferation at each differentiation stage. Disruption of the control mechanism can lead to tumor growth or tissue degeneration. The germline stem cell lineage of Drosophila spermatogenesis provides an ideal research model to unravel the genetic network coordinating proliferation and differentiation. In a genetic screen, we identified a male-sterile mutant whose germ cells are under-differentiated and overproliferating. The responsible gene encodes an RNA-binding protein whose target belongs to a tumor suppressor family. We demonstrate that this and two other RNA-binding proteins form a physical and functional unit to ensure the proper differentiation and accurate proliferation of germline stem cell lineage.
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影响因子：
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作者：
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