The role of miRNAs in the evolution of mammal implantation.

大约1.6亿年前，兽类（有袋类和真兽类）哺乳动物的共同祖先放弃了产卵，进化出了一套完全独特的后代发育系统。这种新的生殖策略包括胚胎植入子宫壁，这是所有哺乳动物成功怀孕所必需的一步。大多数哺乳动物的妊娠流产发生在这一阶段，提高我们对所涉及的机制的理解将对人类的生育和繁殖以及其他方面产生重大影响，牲畜管理，可持续农业和保护濒临灭绝的哺乳动物的努力取决于成功的植入和妊娠。虽然所有的兽类哺乳动物都有正确植入的要求，但不同物种之间的差异在于植入的确切时间（例如，人类大约在第7天左右，但奶牛这个过程需要长达三周的时间），胚胎在子宫内膜内的位置，以及随后发育的胎盘形态。换句话说，植入过程的某些部分是保守的，可能还有一些其他部分是特定哺乳动物所特有的。我们希望从分子水平上了解是什么控制了哺乳动物着床策略的相似性和差异性。在这里，我们关注的是一组小而强大的分子，称为microRNAs，它可以（以动态和高度敏感的方式）控制细胞/器官中产生的蛋白质。microrna的主要运作模式是阻止特定靶蛋白的生成。已知的microRNA基因有数千种，有些是物种间共有的，有些是物种特有的。已知mirna在动物新表型进化的关键时间点出现-暗示它们在新表型/形态的进化中，例如着床的起源。我们已经在实现我们的目标方面取得了重大进展，例如，我们知道特定的miRNA在植入过程中起着关键作用，我们知道在子宫起源时改变其功能并在子宫中表达的特定蛋白质，我们知道控制这些miRNA表达的是什么，我们已经预测了miRNA目标如何在物种之间发生变化。我们还开发了协议、代码和技术，使我们能够开展这项工作。幸运的是，为大量哺乳动物提供基因组资源的主要国际努力已经完成，为我们提供了前所未有的能力来比较大约240种真兽哺乳动物物种的模式。Forde博士使用并开发了特定类型的技术（组学，体外模型）来帮助解决子宫环境和胚胎如何在包括牛和人类在内的许多物种中相互作用的问题。奥康奈尔博士的研究涉及哺乳动物之间是如何相互联系的，基因的功能是如何随着时间而变化的，以及物种的基因组是如何做出反应和适应的。本提案结合了这两个领域的专业知识和优秀的资源，以解决监管创新如何影响哺乳动物着床策略的起源和随后的多样化的基本问题。

About 160 million years ago the common ancestor of therian (marsupials and eutherian) mammals left egg-laying behind and evolved a completely unique system for developing offspring. This new reproductive strategy involved the embryo implanting in the wall of the uterus, a step which is necessary for successful pregnancy in all mammals. The majority of mammal pregnancy loss occurs at this stage, and improving our understanding of the mechanisms involved will have significant impact in human fertility and reproduction and beyond, with livestock management, sustainable agriculture, and conservation efforts for extinction-risk mammals dependent upon successful implantation and pregnancy. Whilst all therian mammals share the requirement for implantation to occur correctly, there are differences between species in terms of precisely when this occurs (e.g. humans at around day 7 but in cows this process takes up to three weeks), what the position of the embryo is within the endometrium, and the morphology of the placenta that subsequently develops. In other words, there are parts of the implantation process that are conserved and there are likely some other parts that are unique to particular mammals. We want to gain molecular level understanding of what controls these similarities and differences in implantation strategy across mammals. Here, we are focussing on a group of small, yet very powerful, molecules called microRNAs that can control (in a dynamic and highly sensitive way) what proteins are made in a cell/organ. The primary mode of operation of microRNAs is to stop a specific target protein being made. There are thousands of known microRNA genes, some are shared between species and some are unique to species. MiRNAs are known to emerge at critical time points in the evolution of novel phenotypes in animals - implicating them in the evolution of novel phenotypes/morphologies e.g. the origin of implantation. We have already made significant progress to meet our goal e.g we know specific miRNAs that are key players in implantation, we know particular proteins that have changed their function at the origin of theria and are expressed in the uterus, we know what is controlling the expression of these miRNAs and we have predicted how the miRNA targets have changed across species. We have also developed the protocols, code, and technologies to enable us to carry out this work. Fortuitously major international efforts to provide genomic resources for large numbers of mammals have completed providing us with unprecedented power to compare patterns across ~240 eutherian mammal species. Dr Forde has used and developed specific types of technology (omics, in vitro models) to help address the question of how the uterine environment and the embryo interact with one another in a number of species including cattle and humans. Dr O'Connell's work has addressed how mammals are related to one another, how the functions of genes change through time and how genomes of species respond and adapt. This proposal marries these two areas of expertise with outstanding resources to address the fundamental question of how regulatory innovations impacted upon the origin and subsequent diversification of implantation strategies in mammals.