Capturing transition states associated with lineag.. (CellStateTransitions)
Capturing transition states associated with lineage decisions in the early mouse embryo
Start date: Jan 1, 2013,
End date: Dec 31, 2014
During early mouse embryogenesis the cells of the blastocyst’s inner cell mass take a lineage decision to contribute either to the epiblast or the primitive endoderm (PE). The allocation of cells to either lineage depends on the activity of FGF signaling and two gene regulatory networks (GRNs), one centered on the transcription factor Nanog, the other one relying on Gata factors. The two GRNs are initially activated in an overlapping and heterogeneous pattern in the ICM, and have been proposed to compete each other out over time. The dynamics of this competition, and how the transition state between the two lineages, marked by co-expression Gatas and Nanog, is resolved, is not known.Here I propose to address these questions in vitro by recapitulating the competition between the Gata- and Nanog-GRNs through the controlled overexpression of Gata factors. This converts embryonic stem cells (ESCs), which contribute primarily to the epiblast when introduced in chimeras, into extraembryonic endoderm (XEN) cells, which contribute solely to PE derivatives. I will combine fluorescent reporters with this ES-to-XEN transition to ask with which dynamics transitions occur in individual cells, whether they involve heterogeneities at the population level, and how these parameters are controlled by the activity of gene regulatory networks and signaling pathways. I will aim at identifying culture conditions that stabilize the transition state, where cells might be on the brink of being XEN, and therefore akin to ICM. I hypothesize, that under these conditions cells will be endowed with higher developmental potential compared to parental ES cells, and be able to contribute to both epiblast and PE-derived tissues.The results of this project will enhance our understanding of the mechanisms underlying lineage decisions in early development and may uncover more general principles that govern the way in which differentiating cells are specified in a stem cell pool.
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