微RNA（miRNAs）、即被认为通过对基因表达的影响参与很多生物过程的非编码RNA的发现，正在改变我们对基因被调控的方式的认识。我们对它们在哺乳动物活体中的功能知之甚少，但新开发的一组能使小鼠的miRNA沉寂的化合物，可为研究它们的功能提供一个强大的工具，也可为使患者的miRNA沉寂提供一个潜在的治疗策略。被称为“antagomirs”的这些新试剂是通过化学方法合成的寡核苷酸，具有与天然miRNA形成互补的序列。对小鼠静脉注射拮抗miR-16、-122、-192 和 -194的“antagomirs”，会使肝脏、肺脏、肾脏、心脏、小肠、脂肪、皮肤、骨髓、肌肉、卵巢和肾上腺等中的相应的miRNA明显减少。（Letter p. 685）在蠕虫和苍蝇中，miRNA在胚胎中具有重要的发育作用。在脊椎动物中，各种不同的发育基因被发现是miRNA调控的直接目标，但此前还没有miRNA在已知的发育过程中起特定作用的例子。现在，这样一个例子已经被找到：miR196在小鼠胚胎中起一个防故障装置的作用，用来确保主要由Hoxb8 和 Shh转录因子调控的基因的准确表达。这一结果支持认为很多脊椎动物的miRNA的功能可能是二级基因调控的观点。
a, Sequence of the 3' UTR of Hoxb8 complements miR-196. An arrow indicates the 5' end of the primary cleavage product. b, 5' RACE analysis in hindlimb and forelimb. Of the 96 hindlimb clones sequenced, 33 yielded a sequence consistent with miR-196-directed cleavage (red); four were also truncated Hoxb8 clones, but cleavage was outside the miRNA-binding site (pink); and 59 were sequences unrelated to Hoxb8 (blue). In the forelimb, no clones were consistent with miR-196-directed cleavage. c, By whole-mount in situ hybridization with a Hoxb8 probe, an expression domain of Hoxb8 was detected in the forelimb field (red bars), but not in the hindlimb field (green bars), of a stage-16 chick embryo (n = 8/8). d, Early pan infection with RCAS::miR-196 resulted in downregulation of Hoxb8 (n = 6/6). e, An RA-soaked bead implanted into the anterior aspect of a stage-22 wild-type forelimb induced Hoxb8 expression (n = 8/10). f, Only marginal induction of Hoxb8 expression was detected on implantation of an RA-soaked bead in a forelimb infected with RCAS::miR-196 (n = 6/8). Anterior view; D, dorsal; V, ventral.
原始出处：
Eran Hornstein, Jennifer H. Mansfield, Soraya Yekta, Jimmy Kuang-Hsien Hu, Brian D. Harfe, Michael T. McManus, Scott Baskerville, David P. Bartel and Clifford J. Tabin. The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development,Nature 438, 671-674
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MiRNA知识介绍
在遗传学, miRNA (微核糖核酸) 是长期以来是典型地20-25 核苷酸唯一搁浅的核糖核酸的形式, 和被认为调控miRNAs 是核糖核酸基因被抄录从DNA, 但不被翻译成蛋白质其它基因的表示。对miRNA 基因比miRNA 编码是更长的DNA 序列。这个DNA 序列包括miRNA 序列和近似反向补全。当这个DNA 序列被抄录成一个唯一搁浅的核糖核酸分子、miRNA 序列和其反向补全基地对形成一个双重搁浅的核糖核酸簪子圈; 这形成一个主要miRNA 结构(pri-miRNA) 。Drosha, 核酵素, 劈开簪子的基地形成pre-miRNA 。Pre-miRNA 分子活跃地然后被运输入中坚力量由Exportin 5, 载体蛋白质。Dicer 酵素然后裁减20-25 核苷酸从簪子的基地发行成熟miRNA 。
MiRNAs 的作用看来是在基因章程。为那个目的, miRNA 是补全对部份的一个或更多信使RNAs (mRNAs), 通常在一个站点在3' UTR 。MiRNA 的焖火对mRNA 禁止蛋白质翻译。在某些情况下, double-stranded 核糖核酸的成立通过miRNA 的捆绑触发mRNA 抄本的退化通过过程相似与核糖核酸干涉(RNAi), 虽则在它被相信的其它案件miRNA 复合体阻拦蛋白质翻译机械或否则防止蛋白质翻译没有导致mRNA 被贬低。
1993 年这个作用第一次被描述了为 蠕虫 Caenorhabditis elegans 由R. C. 李哈佛大学。2002 年自, miRNAs 被证实了以各种各样的植物和动物, 包括 C. elegans、人和工厂 Arabidopsis thaliana。基因被发现了在是相似在感觉的细菌他们控制mRNA 丰盈或翻译由束缚mRNA 由基本配对, 然而他们一般不认为是miRNAs 因为Dicer 酵素不是包含的。
条款 miRNA 第一次被介绍了在一套三项条款在科学(2001 十月26 日)
在工厂中, 所谓的 siRNAs 使用防止病毒核糖核酸的副本。然而这siRNA double-stranded, 机制似乎紧密地与那miRNA 相关, 特别是采取簪子结构入帐户siRNAs 并且被利用调控多孔的基因, 如同miRNAs 。
参考
本文定义miRNA 和提出指南随后而来在分类核糖核酸基因作为miRNA 。胜者Ambros, 健美的Bartel, 大卫P. Bartel, 克里斯托弗·B. Burge, 詹姆斯·C. Carrington, Xuemei Chenand, Gideon ·Dreyfuss, 夏恩·R. Eddy, Sam ·Griffiths 琼斯, Mhairi 马歇尔, Marjori Matzke, 加利Ruvkun 和托马斯·Tuschl (2003)"一个一致的系统为microRNA 注释", 核糖核酸, 9: 277-279 。 链接 本文讨论miRNA 和siRNAs 被介入的过程, 就2 项条款状况在学报科学的同样问题 。大卫Baulcombe (2002)"核糖核酸微观世界", 科学, 297: 2002-2003 。 链接 本文描述在林的 发现4 上, 第一miRNA 被发现(编者按: 实际上, Wikipedia 编辑未读本文, 只有做的推断从传票) 。李、R.C. 、Feinbaum 、R.L. 和Ambros, V. (1993)" C. elegans heterochronic 基因 林4 输入小RNAs 以antisense 互补性对 林14", 细胞, 75: 843854. 链接
相关报道：
基础知识
·什么是miRNAs?
·miRNA:一种新的基因表达调节子
·miRNA是一类小分子RNA
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实验方法
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通讯作者实验室介绍：
Harvard Medical School
New Research Building, 3rd Floor
77 Avenue Louis Pasteur
Boston MA 02115
Tel: (617) 432-7618
Fax: (617) 432-7595
Email: tabin@genetics.med.harvard.edu
8 postdoctoral fellows, 5 graduate students
The laboratory studies the genetic basis by which form and structure are regulated during vertebrate development. We combine classical methods of experimental embryology with modern molecular and genetic techniques for regulating gene expression during embryogenesis.
One of the classic systems for the study of embryonic development is the chick embryo, where grafting experiments have given profound insight into such questions as the patterning of developing limb axes, and the control of organogenesis. These classical experiments provide a context for interpreting modern molecular studies and the methods they employed also give us an additional set of tools for manipulating the embryo. For example, we can use retroviral vectors to alter gene expression in the context of specific transplantations or extirpations. Important complementary information is gained from studies taking advantage of the powerful techniques for regulated misexpression and gene deletion in the mouse.
The lab has major efforts underway exploiting these approaches to understand limb development, from the establishment of the initial axes, to understanding the difference in genetic controls between an arm and a leg, through later specific events such as differential bone growth and specific muscle patterning; and to understand the establishment of left-right asymmetry (e.g.. why your heart is on the left and not the right) from the initiation of the left-right difference, through signaling cascades, to left- or right-specific morphogenesis. We also currently have projects looking at the differentiation of the somites and morphogenesis of the heart, as well as biochemical analysis of the hedgehog signal transduction system, a key signaling pathway during development. In addition, we have evolutionary projects examining the developmental and genetic basis for the morphological variation seen in Darwin's Finches and in cave fish.
References:
Kardon, G., Harfe, B. and Tabin, CJ., ?A Tcf4-Positive Mesodermal Population Provides a Prepattern for Vertebrate Limb Muscle Patterning. Developmental Cell 2003, December;5:937-944
Harfe, BD., Scherz, PJ., Nissim, S., Tian, H., McMahon, AP. and Tabin, CJ. ?Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 2004, August;118(4):517-528
Abzhanov, A., Protas, M., Grant, R., Grant, P. and Tabin, CJ. Bmp4 and morphological variation of the beaks of Darwin's Finches. Science 2004, September;305(5689):1462-1465
