In our research we aim to identify the critical stages in early mammalian development (before implantation) when important decisions for further development take place. Determining critical moments of development when embryos may be more prone to damage is vital for improving the efficiency and safety of assisted reproduction procedures for human embryos and also for better efficiency of these techniques in domestic animals or wild species of mammals (where assisted reproduction techniques can be used for preservation of endangered species). Early mammalian development is very unique among other species. In this system, establishment of body axis and the specification of cell fate are not driven by the segregation of maternally-inherited determinants but rather depend on cell-cell communication during early stages of development. Our current research concentrates on determination of the developmental stage when cells begin to lose plasticity (ability to contribute to all embryonic and extra-embryonic lineages) and become committed to a particular lineage. We also work to determine whether the signals initiating early lineage specification come from cell-cell and cell-environment interaction or whether the process remains under the genetic control of transcriptional factors. W also investigate what factors are crucial for the stabilisation of cell fate during development.
The dynamic of cell fate decision in preimplantation mammalian development
My lab is interested in processes leading to the acquisition of lineage identity and commitment during early mammalian development, as well as in various aspects of regulative abilities of early mammalian embryos. In particular, we are focused on temporal control of the first cell fate decisions during preimplantation mouse development and what is the role of cell-cell communication, cell plasticity and cell cycle in this process.
Our work has challenged the existing model of epiblast and hypoblast specification and demonstrated that stochastic expression of lineage specific transcription factors precedes the maturation of mutually inhibitory regulatory pathways. We have also shown that early cell fate decision are heterochronic and that epiblast precursors (the pluripotent lineage) exhibit reduced plasticity compared with the precursors of extraembryonic lineage – hypoblast (PrE). Our data support the notion that the cell determination is a gradual process and that cells becomes irreversible only at later stages of development Thus, the populations of presumptive PrE and EPI cells may be in different stages of the commitment process. Our results also suggest that the segregation of first lineages is driven by additional regulatory events, including the sensing of positional information that results in up- and down-regulation of key transcription factors. Interfering with positional information provided by cell polarity results in changes in expression and localisation of lineage-specific transcription factors.
Although the emergence of all three embryonic lineages is a common phenomenon among mammals, there are apparent differences observed during lineage specification between different mammalian species. Recently, it was reported that the role of FGF/ERK signalling in the specification of hypoblast and pluripotentcy, well established in mice, may not be conserved in human embryos. Therefore, we are looking for the shared, interspecies mechanisms of the mammalian early lineage specification using mouse and rabbit model. Our recent research suggests that pluripotency-related transcription factor, Sox2, might play a conserved role in epiblast specification in mammals. We also found that aPKC is necessary for survival and correct positioning of hypoblast cells and that the inhibition of aPKC activity during epiblast and hypoblast segregation affects the maturation of hypoblast precursors. Recent derivation of naïve human ES cells using aPKC inhibitors suggests that aPKC function in epiblast and hypoblast specification may be conserved among mammals.
Currently, we investigate the role of ERK signaling in a temporal control of early developmental events, the role of cell cycle in cell fate decisions and role of the physical forces and mechanics in regulating the embryo development and cell fate decisions. We also work on identifying the developmental point upon which the cells become irreversibly committed to the first three embryonic lineages, and factors that contribute to this decisions.