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

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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.