The Road from Pluripotency to Lineage Determination. (360G-Wellcome-091484_Z_10_Z)

Pluripotency is the capacity of individual cells to initiate all lineages of the mature organism in response to signals from the embryo or cell culture environment. Pluripotency has no predetermined programme; it is a tabula rasa. This is the foundation of mammalian development and of embryonic stem (ES) cell biology. Genetic and cell biological studies point to transcription factor command rather than epigenetic governance of the pluripotent state. Persuasive support for this view comes from th e demonstration that pluripotency can be recreated from somatic cells through transcription factor induced reprogramming. We now wish to investigate the other side of this coin; how pluripotent cells exit from a naive ground state and become committed to different lineages. Our hypothesis is that fibroblast growth factor stimulation of the mitogen activated protein kinase cascade perturbs the ground state and creates a metastable condition in which cells are poised for multilineage commitment. W e aim to isolate cells in this transition state and interrogate their regulatory circuitry at both population and single cell levels using quantitative transcriptomics, proteomics and biochemistry, complemented by genetic manipulation and live cell tracking. Through these studies we hope to deepen understanding of the underlying design principles of pluripotency lineage choice.