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离开了产卵，并进化出了一种完全独特的后代发育系统。这一新的生殖策略包括将胚胎植入子宫壁，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损失发生在这个阶段，提高我们对其中涉及的机制的了解将对人类的生育和生殖以及其他方面产生重大影响，包括牲畜管理、可持续农业以及依赖于成功植入和怀孕的灭绝风险哺乳动物的保护工作。虽然所有兽类动物都有正确着床的条件，但不同物种在准确时间上存在差异(例如，人类在第7天左右，但奶牛的这一过程需要长达三周)，胚胎在子宫内膜中的位置，以及随后发育的胎盘的形态。换句话说，植入过程中有一些部分是保守的，可能还有一些其他部分是特定哺乳动物所独有的。我们想要在分子水平上了解是什么控制了哺乳动物之间植入策略的这些相似和不同。在这里，我们关注的是一组被称为microRNAs的小但非常强大的分子，它们可以(以动态和高度敏感的方式)控制细胞/器官中制造什么蛋白质。MicroRNAs的主要工作模式是阻止特定目标蛋白的合成。已知的microRNA基因数以千计，有些是物种间共有的，有些是物种独有的。众所周知，miRNAs出现在动物新表型进化的关键时间点--这意味着它们与新表型/形态的进化有关，例如植入的起源。我们已经取得了重大进展来实现我们的目标，例如，我们知道特定的miRNAs是植入中的关键角色，我们知道特定的蛋白质在子宫起源时改变了它们的功能并在子宫中表达，我们知道是什么控制了这些miRNAs的表达，我们已经预测了miRNA靶标在不同物种中的变化情况。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重大国际努力已经完成，这为我们提供了前所未有的力量来比较约240种真兽类哺乳动物的模式。Forde博士使用并开发了特定类型的技术(组学、体外模型)，以帮助解决包括牛和人类在内的许多物种的子宫环境和胚胎如何相互作用的问题。奥康奈尔博士的工作解决了哺乳动物之间的关系，基因的功能如何随着时间的推移而变化，以及物种的基因组如何响应和适应。这项建议将这两个专业领域与杰出的资源结合在一起，以解决监管创新如何影响哺乳动物植入策略的起源和随后的多样化这一根本问题。

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.