In the original GRAIN project, we set out to define the gene regulatory network (GRN), i.e. the downstream set of genes that interact with one another to control a process, activated in the development of mesencephalic dopaminergic neurons, the cell type affected in Parkinson’s disease. Such network is driven by HES1, a downstream effector of Notch receptors, which mediates cell-cell contact dependent signalling and is crucial for fine tuning the balance between the maintenance of an adequate progenitor pool and the initiation of differentiation in many tissues. Due to unforeseen circumstances, six months within the start of the fellowship the project was subjected to a forced refocusing. Together with the new supervisor, we devised a project that addressed similar overarching questions and aims, in the context of a different signalling pathway (FGF/Erk signalling instead of Notch) and at a different developmental stage: the transition from naïve stem cells to primitive endoderm.
During development, a single cell gives eventually rise to an embryo and its extraembryonic, supportive tissues. This process is highly inefficient, as only 30-40% of conceptions will lead to live births. Recent studies have highlighted an association between correct specification of primitive endoderm (PrE), a tissue that will become the yolk sac, and successful embryo implantation. On a molecular level, it’s been shown that these cells are, to some extent, plastic: they maintain the potential to regenerate themselves and other cell types. How is this possible? Recent research from the Brickman group has revealed that some pluripotency factors, such as Sox2, presumably more active in stem cells and gradually repressed in more differentiated tissues, like PrE, remain bound to their target genes even after the differentiation into PrE has begun. We hypothesize this could be a mechanism to allow for the memory of a previous plastic state.
While the project tackles a fundamental question in biology, its results will help discover biomarkers or druggable targets that will become candidates for future translational research in the context of in vitro fertilization, to maximise successful embryo implantation.
