OOCSOCS · Socs3 gene in oocyte maturation and fertilisation - a novel link between inflammation and infertility

Socs3 gene in oocyte maturation and fertilisation - a novel link between inflammation and infertility

Approximately one in six couples worldwide experience infertility problems. One of the biggest risk factors is female age, affecting the oocyte and consequently the embryo quality, as well as the correct functions of placenta. As the average age of women at the first pregnancy increases, fertility issues are expected to become even more frequent, resulting in clinical consequences for assisted reproductive technology treatments. In order to effectively treat fertility problems, it is crucial to understand molecular mechanisms of oogenesis and early embryonic development. Due to clear ethical considerations associated with research on humans, the mouse is a suitable model for such studies as it shares mechanistic characteristics of oocyte and embryonic development, as well as age-associated fertility problems, with humans. Reproductive aging and problematic female fertility are linked to increased inflammatory signalling. We initially focused on a previously identified candidate gene involved in the regulation of the inflammatory response, as well as placenta development, Suppressor of cytokine signalling 3 (Socs3). However, our research led us towards a much more fundamental role of the mTOR intra-cellular signalling pathway, also associated with inflammation and aging. Specifically, we studied the process of mTOR-regulated cap-dependent translation (a specialized and highly regulated form of cellular protein synthesis) and its effect on the oocyte maturation and the preimplantation embryonic development stages. We uncovered a novel fundamental effect of mTOR signalling on the spatial positioning of cells in the early embryo. Such spatial positioning is tightly associated with the segregation of individual and functional specialization of distinct cell lineages in the early embryo and mTOR signalling regulates the number of the progenitor cells that will give rise to the embryo itself (found encapsulated inside the developing embryonic mass), as oppose to outer-residing cells that ultimately form extraembryonic tissue (i.e. placenta). We also developed a highly optimised low input protocol for genome-wide profiling of actively translated mRNAs (molecular intermediates between genes and synthesis of the proteins they encode), applied it to maturing mouse oocytes and identified important differences in those from aged versus young females; with potential consequences for fertility. In addition, we studied the novel interplay of the mTOR and p38-mitogen-activated-kinase pathways in translation regulation at the late blastocyst stage (i.e. prior to uterine implantation), affecting the specification of the primitive endoderm extraembryonic cell lineage (needed to support the post-implantation developmental stages). As a direct consequence of this award and the above summarised experiments progression, this project has also substantially contributed to the career progression of the postdoctoral researcher, Dr. Gahurova, towards becoming an independent group leader at the University of South Bohemia in Czech Republic.

Data: CORDIS, © European Union