Developmental roadmap of primordial germ cells in humans and pigs

研究哺乳动物中配子的发育，即制造卵子和精子的细胞，对于理解动物发育和进化的基础非常重要。它在生物技术、辅助生殖、物种保护和再生医学方面也有重要的应用。我们和其他人已经证明，生殖细胞前体，即原始生殖细胞（PGCs），出现在大型哺乳动物（如猪和非人灵长类动物）早期胚胎的后部区域，并且控制生殖细胞前体发育的关键基因在这些物种中是保守的。虽然PGC形成的时期是已知的，但对诱导信号作出反应的细胞的特征是未知的。在这个项目中，我们将测试一个假设，即位于胚胎后端的具有独特分子特征的细胞可以响应特定信号形成生殖细胞前体。我们将进行实验，以建立胚胎中PGC前体的遗传和表观遗传特征，并使用猪外胚层干细胞和人胚胎干细胞进行功能实验，以确定生殖细胞发育的关键主调节因子。该项目的结果将帮助我们详细了解PGC是如何从祖细胞库中诱导出来的。这将通过绘制猪PGC及其前体的遗传和表观遗传特征来实现，以建立其发育进程的图谱，并通过使用干细胞进行实验来确定调节这一过程的关键主基因（SOX 17）的作用。有趣的是，主调节器SOX 17参与生殖细胞和肠道祖细胞的程序。在这里，我们将确定这种蛋白质如何引起对周围组织中产生的诱导信号的差异反应，以启动胚胎中两种不同的分化程序。这些全面的研究将首次提供对大型哺乳动物PGCs形成的详细分子理解。这一新的知识将是重要的，为建立改进的方法，从人类和牲畜物种的干细胞研究人类PGC的发展。开发新技术，使配子的产生在实验室中将有广泛的应用，了解人类不育的原因，通过配子发生模型，获得更好地了解生殖细胞肿瘤的起源，并在牲畜辅助生殖。该项目涉及BBSRC职权范围内的战略相关性问题，如终身健康和福祉。我们预计，当前项目的成果将有助于再生医学和全球粮食安全领域的学术和临床进步。

Studying the development of the gametes, the cells that make egg and sperm, in mammals is important for understanding the basis of animal development and evolution. It also has important applications in biotechnology, assisted reproduction, species conservation and regenerative medicine.We and others have shown that germ cell precursors, the primordial germ cells (PGCs), emerge in the posterior region of early embryos in large mammals (e.g. pigs and non-human primates), and that key genes that control development of germ cell precursors is conserved in these species. Although the period when PGC form is known, the features of the cells that respond to inducing signals is unknown. In this project we will test the hypothesis that cells with a unique molecular signature localized in the posterior end of the embryo can respond to specific signals to form germ cell precursors. We will carry out experiments to establish the genetic and epigenetic profile of PGC precursors in an embryo, and functional experiments using pig epiblast stem cells and human embryonic stem cells to identify key master regulators of germ cell development. The results of the project will help us gain a detailed understanding of how PGCs are induced from a pool of progenitor cells. This will be achieved by mapping the genetic and epigenetic signatures of pig PGCs and their precursors to build an atlas of their developmental progression, and by performing experiments using stem cells to identify role of a key master gene (SOX17) regulating this process. Intriguingly, the master regulator SOX17 is involved in the program of germ cells and gut progenitors. Here we will determine how this protein can elicit a differential response to inducing signals produced in the surrounding tissues to initiate two different programs of differentiation in an embryo. These comprehensive investigations will provide detailed molecular understanding of the formation of the PGCs in a large mammal for the first time. This new knowledge will be important for establishing improved methodologies for the study of human PGC development from stem cells in humans and livestock species. Development of new technologies that allow the generation of gametes in the laboratory will have broad applications for understanding the causes of infertility in humans through modelling of gametogenesis, for gaining better understanding of the origin of germ cell tumours, and for assisted reproduction in livestock. This project addresses questions of strategic relevance in the BBSRC remit, such as lifelong health and wellbeing. We anticipate that the outcomes of the current project will contribute to the academic and clinical advance in the areas of regenerative medicine and global food security.