Pvr expression regulators in equilibrium signal control and maintenance of Drosophila blood progenitors.
Pvr expression regulators in equilibrium signal control and maintenance of Drosophila blood progenitors.
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DOI：
10.7554/elife.03626
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发表时间：
2014-09-08
期刊：
影响因子：
7.7
通讯作者：
Banerjee U
中科院分区：
文献类型：
--
作者：
Mondal BC;Shim J;Evans CJ;Banerjee U
淋巴腺是果蝇的一个支持造血的幼虫器官，淋巴腺内的血液祖细胞通过整合来自小生境样细胞和分化中的血细胞的信号来维持。我们将来自分化细胞的信号称为“平衡信号”，以将其与“小生境信号”区分开。早期，我们发现平衡信号利用Pvr（果蝇PDGF/VEGF受体），STAT 92 E和腺苷脱氨酶相关生长因子A（ADGF-A）。关于这个信号在造血发育过程中是如何启动的，我们知之甚少。为了鉴定参与淋巴腺血液祖细胞维持的新基因，特别是那些参与平衡信号传导的基因，我们进行了一项遗传筛选，将bip 1（bric à brac相互作用蛋白1）和Nucleoporin 98（Nup 98）鉴定为平衡信号的额外调节因子。我们发现，这些基因的产物沿着与Bip 1相互作用的蛋白RpS 8（核糖体蛋白S8）是Pvr的正确表达所必需的。http://dx.doi.org/10.7554/eLife.03626.001祖细胞是一种既可以复制自己的细胞，也可以成熟为不同的特殊细胞类型，如血细胞。在果蝇Drosophila中，新的血细胞在几个不同的位置形成，包括在称为淋巴腺的器官中。2011年，研究人员发现淋巴腺内血液祖细胞的命运由来自附近两个来源的信号控制--一个来自专门的支持性（“利基”）细胞，另一个来自成熟的血细胞。来自成熟血细胞的信号确保祖细胞和成熟血细胞的相对量保持在正确的平衡中。因此，这种信号传递过程被称为“均衡信号传递”。问题仍然是如何平衡信号调节，以及它如何与来自利基的信号相互作用。为了研究这个问题，Mondal等人-包括参与2011年工作的一些研究人员在内，他们使用各种遗传技术创造了果蝇幼虫，在果蝇幼虫中，形成血细胞的组织用荧光蛋白可见。这意味着这些组织可以通过显微镜在活的整个动物中进行检查。Mondal等人随后寻找果蝇中参与淋巴腺生成新血细胞的基因，特别是那些参与平衡信号传导的基因。这是通过在淋巴腺中一个接一个地打开和关闭数百个基因来完成的，然后进一步研究导致新血细胞生成变化的任何基因。在这些研究之后，Mondal等人集中在三个基因上，当这些基因中的每一个在成熟的血细胞中被关闭时，结果是留在淋巴腺中的祖细胞更少。当这些基因在祖细胞或小生境细胞中被关闭时，没有看到这种效果，这表明这些基因可能是平衡信号通路的组成部分。关闭成熟血细胞中的这些基因也大大降低了一种名为Pvr的蛋白质的水平，Pvr是2011年研究中已知的一种关键平衡信号蛋白，也是几个物种血细胞发育的重要参与者。新发现的基因如何实际控制Pvr蛋白水平以维持淋巴腺中适当的平衡信号传导仍有待探索。然而，这项工作为研究相关基因在脊椎动物系统（即人类）血细胞发育中的作用提供了基础。DOI：http://dx.doi.org/10.7554/eLife.03626.002网站
Blood progenitors within the lymph gland, a larval organ that supports hematopoiesis in Drosophila melanogaster, are maintained by integrating signals emanating from niche-like cells and those from differentiating blood cells. We term the signal from differentiating cells the ‘equilibrium signal’ in order to distinguish it from the ‘niche signal’. Earlier we showed that equilibrium signaling utilizes Pvr (the Drosophila PDGF/VEGF receptor), STAT92E, and adenosine deaminase-related growth factor A (ADGF-A). Little is known about how this signal initiates during hematopoietic development. To identify new genes involved in lymph gland blood progenitor maintenance, particularly those involved in equilibrium signaling, we performed a genetic screen that identified bip1 (bric à brac interacting protein 1) and Nucleoporin 98 (Nup98) as additional regulators of the equilibrium signal. We show that the products of these genes along with the Bip1-interacting protein RpS8 (Ribosomal protein S8) are required for the proper expression of Pvr. DOI: http://dx.doi.org/10.7554/eLife.03626.001 Progenitor cells are cells that can either multiply to make new copies of themselves or mature into different specialized cell types—such as blood cells. In the fruit fly Drosophila, new blood cells are formed in several different locations, including in an organ called the lymph gland. In 2011, researchers found that the fate of blood progenitor cells within the lymph gland is controlled by signals from two nearby sources—one from specialized, supportive (‘niche’) cells and the other from maturing blood cells. The signal from the maturing blood cells ensures that the relative amounts of progenitor and maturing blood cells are kept in the right balance. As a result, this signaling process has been called ‘equilibrium signaling’. Questions remain as to how equilibrium signaling is regulated, and how it interacts with signals from the niche. To investigate this, Mondal et al.—including some of the researchers involved in the 2011 work—used various genetic techniques to create Drosophila larvae in which the tissues that become blood cells are made visible with fluorescent proteins. This meant that these tissues could be examined in live, whole animals by using a microscope. Mondal et al. then searched for the Drosophila genes involved in generating new blood cells in the lymph gland—particularly those involved in equilibrium signaling. This was done by switching on and off hundreds of genes, one by one, in the lymph gland, and any genes that caused changes to the generation of new blood cells were then investigated further. Following these investigations, Mondal et al. focused on three genes—and when each of these genes was switched off in maturing blood cells, the result was that fewer progenitor cells remained in the lymph gland. This effect was not seen when the genes were switched off in the progenitor or the niche cells, which suggested that the genes are likely to be components of the equilibrium signaling pathway. Switching off these genes in maturing blood cells also dramatically reduced the levels of a protein called Pvr, a key equilibrium signaling protein known from the 2011 study and an important player in blood cell development in several species. How the newly identified genes actually control Pvr protein levels to maintain proper equilibrium signaling in the lymph gland remains to be explored. However, this work provides a basis for investigating the role of related genes in blood cell development in vertebrate systems, namely humans. DOI: http://dx.doi.org/10.7554/eLife.03626.002