Award details

The role of miRNAs in the evolution of mammal implantation.

Reference	BB/X007367/1
Principal Investigator / Supervisor	Professor Niamh Forde
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	School of Medicine
Funding type	Research
Value (£)	599,282
Status	Current
Type	Research Grant
Start date	01/04/2023
End date	31/03/2026
Duration	36 months

Abstract

The embyros of all therian mammals (marsupials and eutheria) must undergo implantation for successful pregnancy to occur but the process has diversified significantly across lineages. The majority of pregnancy loss occurs around this time and is when life-course health can be determined. The goal of this proposal is to achieve molecular-level understanding of the origin and diversification of implantation strategies across mammals. To achieve this we are focussing on a set of microRNA (miRNA) genes whose origins are co-incident with the origin of mammals and how they mediate implantation in eutherian mammals. MiRNAs are endogenous RNAs that carry out posttranscriptional repression or decay of protein-coding mRNA and lncRNAs and they play a pervasive role in regulating key processes such as cellular processes of proliferation, differentiation and apoptosis. MiRNAs have been tightly associated with the evolution of complexity. We have already identified a subset of 17 out of a total of 54 miRNA genes that emerged coincident with the origin of therian mammals and to our knowledge were never subsequently lost. Most recently we have shown some are regulated by molecular cues important for endometrial receptivity to implantation. We have established that these miRNA genes are predicted to target genes that (i) have undergone positive selection, and (ii) gained uterine expression on the stem lineage. Our key research questions are: 1. What are the conservation and divergence patterns of miRNA genes that arose at the origin of placental mammals? 2. What are the targets of the conserved miRNAs and how have they changed across mammals? 3. Do changes in miRNA repertoire tally with observed implantation and placental phenotypic variation through time? 4. What are the functions and mechanisms of action of miRNAs in diverse implantation strategies in placental mammals?

Summary

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 ourgoal 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.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/X007332/1 The role of miRNAs in the evolution of mammal implantation.

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search