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

胎生在脊椎动物中独立进化了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，在干细胞胎盘哺乳动物谱系中，胚胎植入的独特过程进化而来。植入是指每4个人类妊娠中就有1个丢失的阶段。植入涉及发育中的胚胎组织和预置的母体结构之间的密切相互作用。虽然在胎盘哺乳动物植入过程的细节上存在一些差异，但在所有情况下，它都会在临时器官-胎盘的发育中达到顶峰。这一进化实验如此成功，以至于哺乳动物的快速辐射接踵而至，胎盘哺乳动物建立了非鸟类始祖龙腾出的各种生态位。哺乳动物生殖策略的这种戏剧性转变的分子基础还没有完全阐明。一种独特的表观遗传现象被称为基因组印记，对哺乳动物的生存至关重要，并出现在干哺乳动物谱系中。基因组印迹导致以亲本方式在整个哺乳动物基因组中以簇状编码的一组元件的单等位基因表达，产生了亲本对资源的拉锯战。我们现在知道，植入在一定程度上是由来自父系的胚胎基因组指导的。我们最近发现了一组13个microRNAs(小调节分子)，它们出现在胎盘哺乳动物的起源，随后从未在任何现存的胎盘哺乳动物物种中丢失。MicroRNAs是具有较短的“种子”序列的短RNA(~22个核苷酸)，它与mRNAs的3‘非翻译区的互补“靶”序列相互作用，导致翻译抑制和/或加速的mRNA衰变。我们已经证明，这13个miRNAs是在一系列哺乳动物物种中对关键的早期怀孕分子做出反应而表达的。这13个miRNAs调控什么？这个整个调控网络在所有现存的哺乳动物中都是保守的吗？这些miRNAs是否倾向于调节整个系统发育过程中的基因组印记区域？父系来源的基因组是优先靶点吗？第一个胎盘哺乳动物的植入过程、基因组印迹景观和胎盘类型是什么？研究哺乳动物的生殖进化并确定怀孕成功的关键分子是农业和粮食安全的关键(例如，猪和牛是食物生产的主要哺乳动物物种)。改进动物克隆和诱导多能干细胞生成的重新编程技术也将直接受益于这项工作。我们正在研究的许多miRNAs与人类反复和/或早孕丢失有关。我们的目标是确定整个调控网络，该网络进化为促进哺乳动物早期着床。这一基础项目将有助于未来对复发性流产的诊断和治疗。最后，目前的灭绝危机对相当数量的哺乳动物来说尤其具有挑战性，随着保护努力的加强，精确的生殖计划战略是成功的关键。

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.