Reconstructing the first true placental mammal: elucidating the molecular evolution of implantation in mammals

重建第一个真正的胎盘哺乳动物：阐明哺乳动物着床的分子进化

• 批准号: 2747603
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2747603
• 关键词: Reconstructing; first; true; placental; mammal

Viviparity has evolved independently over 100 times across vertebrates, e.g. in reptiles, amphibia, and mammals. However, some ~150 million year ago in the stem placental mammal lineage the unique process of embryonic implantation evolved. Implantation is the stage in which 1 in 4 human pregnancies are lost. Implantation involves intimate interaction between the developing embryonic tissue and primed maternal structures. Whilst some variation exists in the finer details of the implantation process across placental mammals, in all cases it culminates in the development of the temporary organ - the placenta. So successful was this evolutionary experiment that rapid mammal radiation ensued, with placental mammals establishing the diverse range of ecological niches vacated by the non-avian archosaurs. The molecular underpinnings of this dramatic shift in reproductive strategy in mammals have not been fully elucidated. A unique epigenetic phenomenon known as genomic imprinting is essential for mammal viability and emerged on the stem mammal lineage. Genomic imprinting results in the monoallelic expression of a subset of the elements encoded in clusters across the mammal genome in a parent of origin manner producing a parental tug of war on resources. We now know that implantation is directed, in part, by the embryos paternally derived genome. We have recently identified a set of 13 microRNAs (small regulatory molecules) that emerged at the origin of placental mammals and were never subsequently lost in any extant placental mammal species. MicroRNAs are short RNAs (~22 nucleotides) with shorter "seed" sequences that interact with complementary "target" sequences in the 3' untranslated regions of mRNAs resulting in translational repression and/or accelerated decay of the mRNA. We have shown that these 13 miRNAs are expressed in response to key early pregnancy molecules in a range of mammal species. What do these 13 miRNAs regulate/control? Is this entire regulatory network conserved across all extant mammals? Do these miRNAs tend to regulate genomically imprinted regions across the phylogeny? Is the paternally derived genome preferentially targeted? What was the implantation process, genomic imprinting landscape and placental type in the first placental mammal? Studying the evolution of reproduction in mammals and identifying molecules central to pregnancy success is key to agricultural and food security (e.g. pig and cow are central mammal species to food production). Improving reprogramming technologies for animal cloning and induced pluripotent stem cell generation will also directly benefit from this work. Many of the miRNAs we are working with are implicated in recurrent and/or early pregnancy loss in human. Our goal is to identify the entire regulatory network that evolved to facilitate early implantation in mammals. This fundamental project will contribute to future diagnostics and treatment of recurrent miscarriage. Finally, the current extinction crisis is particularly challenging for a significant number of mammals, and precise strategies for reproductive programs is key to success as conservation efforts intensify.

脊椎动物的胎生已经独立进化了 100 多次，例如：在爬行动物、两栖动物和哺乳动物中。然而，大约1.5亿年前，干胎盘哺乳动物谱系中进化出了独特的胚胎着床过程。着床是四分之一的人类妊娠失败的阶段。着床涉及发育中的胚胎组织和已启动的母体结构之间的密切相互作用。虽然胎盘哺乳动物的着床过程的细节存在一些差异，但在所有情况下，最终都会形成临时器官——胎盘。这项进化实验非常成功，导致哺乳动物迅速辐射，胎盘哺乳动物建立了非鸟类祖龙腾出的各种生态位。哺乳动物生殖策略这一巨大转变的分子基础尚未完全阐明。一种被称为基因组印记的独特表观遗传现象对于哺乳动物的生存至关重要，并且出现在哺乳动物的干系中。基因组印记导致哺乳动物基因组中以亲本方式编码的元素子集的单等位基因表达，从而产生亲本对资源的拉锯战。我们现在知道，植入部分是由胚胎的父系基因组指导的。我们最近鉴定了一组 13 个 microRNA（小调节分子），它们出现在胎盘哺乳动物的起源中，并且随后在任何现存的胎盘哺乳动物物种中从未消失。 MicroRNA 是短 RNA（约 22 个核苷酸），具有较短的“种子”序列，可与 mRNA 3' 非翻译区中的互补“靶”序列相互作用，导致 mRNA 的翻译抑制和/或加速衰减。我们已经证明，这 13 种 miRNA 在一系列哺乳动物物种中表达，以响应关键的早期妊娠分子。这 13 种 miRNA 调节/控制什么？这整个调控网络在所有现存哺乳动物中都是保守的吗？这些 miRNA 是否倾向于调节整个系统发育的基因组印记区域？父系来源的基因组是优先靶向的吗？第一个胎盘哺乳动物的着床过程、基因组印记景观和胎盘类型是怎样的？研究哺乳动物繁殖的进化并确定对成功怀孕至关重要的分子是农业和粮食安全的关键（例如猪和牛是粮食生产的核心哺乳动物物种）。改进动物克隆和诱导多能干细胞生成的重编程技术也将直接受益于这项工作。我们正在研究的许多 miRNA 与人类复发性和/或早期妊娠流产有关。我们的目标是确定为促进哺乳动物早期植入而进化的整个调控网络。这一基础项目将有助于未来复发性流产的诊断和治疗。最后，当前的灭绝危机对大量哺乳动物来说尤其具有挑战性，随着保护工作的加强，精确的繁殖计划策略是成功的关键。