lin-28 controls the succession of cell fate choices via two distinct activities.
lin-28 controls the succession of cell fate choices via two distinct activities.
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DOI：
10.1371/journal.pgen.1002588
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Moss EG
中科院分区：
文献类型：
--
作者：
Vadla B;Kemper K;Alaimo J;Heine C;Moss EG
lin-28是动物中细胞命运演替的保守调节因子。在秀丽隐杆线虫中，它是控制幼虫发育时间的异时基因途径的一个组成部分，而其脊椎动物同源物促进多能性并控制不同组织的分化。lin-28编码的RNA结合蛋白可以通过一种新的机制直接抑制let-7 microRNA的加工，这种机制从蠕虫到人类都是保守的。我们发现C.线虫LIN-28蛋白可以与四种不同的let-7家族前体microRNA相互作用，但在体内仅抑制let-7的过早积累。然而，令人惊讶的是，lin-28并不需要let-7或它的亲戚来促进第二幼虫期细胞的命运。换句话说，我们发现成熟let-7的过早积累不能解释lin-28的早熟表型。为了解释let-7在lin-28活性中的作用，我们提供了lin-28通过两个步骤起作用的证据：首先，hbl-1通过其3′UTR控制L2阶段特异性细胞命运的let-7非依赖性正调控;第二，let-7依赖性步骤，通过lin-41的抑制控制随后的命运。我们的证据还表明let-7在C中提前一个阶段起作用。比以前想象的要好。重要的是，lin-28的两步机制类似于异时基因lin-14，它们活动的重叠表明了发育时间的时钟机制。此外，该模型解释了先前观察到的哺乳动物Lin 28具有两种遗传上可分离的活性。因此，lin-28的两步机制可能是其在细胞命运演替中进化保守作用的一个基本特征。随着组织的形成，不同的细胞类型从一个共同的未分化细胞库中产生。控制这种发育时间的机制在很大程度上是未知的。在秀丽隐杆线虫中，异时基因控制着幼虫逐渐分化组织中细胞命运的连续变化。其中两个基因lin-28和let-7在动物中进化上是保守的，它们在多能性和分化中发挥作用。已知LIN-28蛋白结合并阻断let-7编码的小RNA的成熟。这种机制似乎可以解释lin-28在发育中的作用。在这里，我们表明，lin-28的主要活动在C。elegans-第二幼虫阶段细胞命运的适当时机-不需要let-7或相关基因。在解释这种差异时，我们提供了lin-28有两种不同的控制连续细胞命运的活性的证据。这种情况与林-14非常相似，林-14的作用比林-14早一个阶段。一个阶段的活动重叠可能反映了这种细胞命运继承机制的一个基本特征。此外，两步机制解释了哺乳动物Lin 28也具有遗传分离活性的观察结果。因此，lin-28的两个连续的活动可能是必不可少的进化保守的作用，在发育时间。
lin-28 is a conserved regulator of cell fate succession in animals. In Caenorhabditis elegans, it is a component of the heterochronic gene pathway that governs larval developmental timing, while its vertebrate homologs promote pluripotency and control differentiation in diverse tissues. The RNA binding protein encoded by lin-28 can directly inhibit let-7 microRNA processing by a novel mechanism that is conserved from worms to humans. We found that C. elegans LIN-28 protein can interact with four distinct let-7 family pre-microRNAs, but in vivo inhibits the premature accumulation of only let-7. Surprisingly, however, lin-28 does not require let-7 or its relatives for its characteristic promotion of second larval stage cell fates. In other words, we find that the premature accumulation of mature let-7 does not account for lin-28's precocious phenotype. To explain let-7's role in lin-28 activity, we provide evidence that lin-28 acts in two steps: first, the let-7–independent positive regulation of hbl-1 through its 3′UTR to control L2 stage-specific cell fates; and second, a let-7–dependent step that controls subsequent fates via repression of lin-41. Our evidence also indicates that let-7 functions one stage earlier in C. elegans development than previously thought. Importantly, lin-28's two-step mechanism resembles that of the heterochronic gene lin-14, and the overlap of their activities suggests a clockwork mechanism for developmental timing. Furthermore, this model explains the previous observation that mammalian Lin28 has two genetically separable activities. Thus, lin-28's two-step mechanism may be an essential feature of its evolutionarily conserved role in cell fate succession. As tissues form, different cell types are generated from a common pool of undifferentiated cells. The mechanisms that control this developmental timing are largely unknown. In the nematode Caenorhabditis elegans, the heterochronic genes control a succession of cell fates in progressively differentiating tissues of the larva. Two of these genes, lin-28 and let-7, are evolutionarily conserved in animals where they have roles in pluripotency and differentiation. The LIN-28 protein is known to bind to and block the maturation of the small RNA encoded by let-7. This mechanism would seem to explain lin-28's role in development. Here we show that lin-28's primary activity in C. elegans—the proper timing of second larval stage cell fates—does not require let-7 or related genes. In explaining this discrepancy, we provide evidence that lin-28 has two distinct activities controlling successive cell fates. This situation is remarkably like that of lin-14, which acts one stage earlier. The overlap of their activities by one stage may reflect a fundamental feature of this cell fate succession mechanism. Furthermore, the two-step mechanism explains observations that mammalian Lin28 also has genetically separable activities. Therefore, lin-28's two successive activities may be essential to its evolutionarily conserved role in developmental timing.
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影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
64.5
作者：
Heo, Inha;Joo, Chirlmin;Kim, V. Narry
通讯作者：
Kim, V. Narry
DOI：
10.1073/pnas.0908131106
发表时间：
2009-11-03
影响因子：
11.1
作者：
Hammell, Christopher M.;Karp, Xantha;Ambros, Victor
通讯作者：
Ambros, Victor
影响因子：
9.2
作者：
Caygill, Elizabeth E.;Johnston, Laura A.
通讯作者：
Johnston, Laura A.
影响因子：
10.5
作者：
AMBROS, V;HORVITZ, HR
通讯作者：
HORVITZ, HR