Abstract
Embryonic stem cells and induced pluripotent stem cells represent potentially important therapeutic agents in regenerative medicine. Complex interlinked transcriptional and signaling networks control the fate of these cells towards maintenance of pluripotency or differentiation. In this study we have focused on how mouse embryonic stem cells begin to differentiate and lose pluripotency and, in particular, the role that the ERK MAP kinase and GSK3 signaling pathways play in this process. Through a genome-wide siRNA screen we have identified more than 400 genes involved in loss of pluripotency and promoting the onset of differentiation. These genes were functionally associated with the ERK and/or GSK3 pathways, providing an important resource for studying the roles of these pathways in controlling escape from the pluripotent ground state. More detailed analysis identified MAP kinase phosphatases as a focal point of regulation and demonstrated an important role for these enzymes in controlling ERK activation kinetics and subsequently determining early embryonic stem cell fate decisions.
Highlights
Embryonic stem cells and induced pluripotent stem cells are currently generating intense interest due to their potential therapeutic roles in regenerative medicine
As our primary interest was on the mechanisms of escape from the pluripotent ground state rather than the maintenance of pluripotency, we subsequently focussed on genes that were required for modulating the onset of differentiation
Numerous studies have helped build up a view of the complex signaling and transcriptional networks involved in maintaining the pluripotent state of embryonic stem cells but in contrast, much less is known about the pathways leading to the loss of pluripotency
Summary
Embryonic stem cells and induced pluripotent stem cells (iPS cells) are currently generating intense interest due to their potential therapeutic roles in regenerative medicine (reviewed in [1]). Mouse embryonic stem cells can be maintained in a pluripotent state by culturing under a variety of defined conditions (reviewed in [7]). More recently, it was demonstrated that mouse embryonic stem cells can be maintained in a pluripotent ground state by using two specific protein kinase inhibitors (known as ‘‘2i’’ conditions) which target the ERK pathway component MEK and glycogen synthase kinase (GSK3) ([10]; reviewed in [11]). Removal of these two inhibitors promotes exit from the naıve ground state. A b-catenin-dependent mode of action has been demonstrated for GSK3 in the context of mouse embryonic stem cells, this mode of action is not sufficient to explain all the effects of GSK3 signalling in this context ([23,24]; reviewed in [25])
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