How does signaling induce human primordial germ cells?

信号传导如何诱导人类原始生殖细胞？

• 批准号: MR/N020979/1
• 负责人: Andrew Johnson
• 金额: $ 90.24万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN020979%2F1
• 关键词: How; does; signaling; induce; human

Primordial germ cells (PGCs) are the cells in an embryo that later become egg and sperm in adults, and they form in the early stages of an embryo's development. Understanding the molecular/genetic mechanism that controls PGC development is important for assisted reproduction, technologies, understanding the origins germ line cancers, and for regenerative medicine. However, to date little is known about how PGCs development in humans is controlled. Indeed, understanding how cells in an embryo decide to become PGCs, in vertebrates, generally, has posed a unique challenge to biologists for reasons that are only now becoming clear. At its heart is the process of evolution, and how evolutionary forces have affected the mechanisms for PGC development. Because, while many mechanisms that control development have been worked out in embryos of simpler animals, like those of frogs or fish, it has not been possible to use these species as "models" for human PGC development. This is because each of the model organisms typically studied in laboratories has evolved a unique mechanism for producing PGCs. Humans, in contrast, employ what is apparently the original mechanism that evolved in vertebrates to produce PGCs, the so-called conserved mechanism. We recognized this problem several years ago, and to explain it we developed a novel theory of evolution concerning the relationship between PGCs and the other cells in an embryo, known as somatic cells. We hypothesized that human embryos retain the mechanism for PGC development that originally evolved in vertebrates, the so-called conserved mechanism. A major component of this theory is, also, that PGCs are derived from the same cells as somatic cells, not from specialized cells. To test this theory, the MRC funded development of an experimental system using embryos from axolotls, a salamander. Axolotls were chosen because they resemble the first vertebrates to move onto land, in other words, the amphibian ancestor to mammals. We predicted that axolotls and humans would share the same mechanism for PGC development, and axolotl embryos could therefore be used as an experimental model to unpick the mechanisms driving this process. We determined the signals that govern PGC development in axolotls, and then considered a an established genetic pathway known to act downstream of these signals in other cell types. From this we identified a principle role for the transcription factor Elk-1, and its functional partner Med23, in PGC development. Elk-1 was discovered over 25 years ago, but its role in embryos has never been clearly determined because commonly studied animal models, including mice, evolved genetic circuits that circumvent its ancient role in embryos. We showed that the pathway discovered in axolotls also controls development of PGCs in pigs, whose embryos accurately model those of humans, strongly suggesting that the role for Elk-1/Med23 that we discovered also directs development of human PGCs. Our proposal is designed to use axolotl embryos to define the biochemical and genetic mechanisms controlling the conserved pathway for vertebrate PGC development. We propose to reduce the activity of Elk-1 or Med23, and replace these proteins with mutant molecules lacking specific biochemical functions. We will also identify all of the genes either up or down-regulated by Elk-1/Med23 that control the distinction of PGCs from somatic cells. We will also test the function of Elk-1/Med23 using newly developed methods to induce PGC-like cells from human embryonic stem cells (hESC), and we will use this hESC system to identify the genetic elements responsible for switching-on genes that regulate human of PGC development. This will be a step towards defining the conserved network of gene required for vertebrate PGC development, enhancing our ability to understand and manipulate germ cells to address issues concerning human health.

原始生殖细胞（PGC）是胚胎中的细胞，后来成为成年人的卵子和精子，它们在胚胎发育的早期阶段形成。了解控制PGC发育的分子/遗传机制对于辅助繁殖，技术，了解起源生殖系癌和再生医学至关重要。但是，迄今为止，关于如何控制人类的PGCS发展知之甚少。确实，了解胚胎中的细胞如何决定成为脊椎动物中的PGC，通常是由于目前越来越清楚的原因，对生物学家提出了一个独特的挑战。它的核心是进化的过程，以及进化力如何影响PGC发展的机制。因为，尽管许多控制发展的机制已经在简单动物的胚胎中（例如青蛙或鱼类的胚胎）进行了，但不可能将这些物种用作人类PGC发育的“模型”。这是因为通常在实验室中研究的每个模型生物已经发展出生产PGC的独特机制。相比之下，人类采用了显然是在​​脊椎动物中进化而来的原始机制来产生PGC，即所谓的保守机制。几年前，我们认识到了这个问题，为了解释这一点，我们开发了一种新的进化论，涉及PGC和其他细胞之间在胚胎（称为躯体细胞）中的关系。我们假设人类胚胎保留了最初在脊椎动物（所谓的保守机制）中进化的PGC发育机制。该理论的一个主要组成部分也是，PGC是从与体细胞相同的细胞而不是专门细胞得出的。为了检验该理论，MRC使用来自salamander的Axolotls的胚胎资助了实验系统的发展。之所以选择Axolotls，是因为它们类似于第一批脊椎动物，换句话说，两栖动物是哺乳动物的两栖动物。我们预测，Axolotls和人类将具有相同的PGC发育机制，因此可以将Axolotl胚胎用作实验模型，以取消驱动此过程的机制。我们确定了控制Axolotls中PGC发育的信号，然后将其视为已知的已知遗传途径，已知在其他细胞类型中的这些信号下游作用。由此，我们确定了转录因子ELK-1及其功能伙伴MED23在PGC开发中的主要作用。 ELK-1是25年前发现的，但是它在胚胎中的作用从未得到明确确定，因为经常研究的动物模型（包括小鼠，进化的遗传回路）绕过其在胚胎中的古老作用。我们表明，在Axolotls中发现的途径还控制着PGC在猪中的发展，猪的胚胎会准确地模拟人类的胚胎，这强烈表明我们发现ELK-1/MED23的作用也是我们发现的，也指导人类PGC的发展。我们的建议旨在使用Axolotl胚胎来定义控制脊椎动物PGC发育的保守途径的生化和遗传机制。我们建议降低ELK-1或MED23的活性，并用缺乏特定生化功能的突变分子代替这些蛋白质。我们还将确定由ELK-1/MED23向上或下调的所有基因，这些基因控制PGC与体细胞的区别。我们还将使用新开发的方法来测试ELK-1/MED23的功能，以诱导人类胚胎干细胞（HESC）诱导PGC样细胞（HESC），我们将使用该hESC系统来识别负责调节PGC发育人类开关基因的遗传元素。这将是定义脊椎动物PGC开发所需的保守基因网络的一步，增强了我们理解和操纵生殖细胞以解决有关人类健康问题的能力。

项目成果

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• DOI: 10.3791/54416
• 发表时间: 2016-08-16
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• 通讯作者: Ruzov A

foxc1a and foxc1b differentially regulate angiogenesis from arteries and veins by modulating Vascular Endothelial Growth Factor signalling

• DOI: 10.1101/417931
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NANOG is required to establish the competence for germ-layer differentiation in the basal tetrapod axolotl.

• DOI: 10.1371/journal.pbio.3002121
• 发表时间: 2023-06
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Cancer reversion with oocyte extracts is mediated by cell cycle arrest and induction of tumour dormancy.

• DOI: 10.18632/oncotarget.24664
• 发表时间: 2018-03-23
• 期刊: Oncotarget
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• 通讯作者: Allegrucci C