title: An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells.
abstract: Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a "race for fates" in which the neuroectodermal fate has an advantage.
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Turner
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Trott
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Hayward
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Pau
authors.initials: P
authors.lastname: Rué
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK ama11@hermes.cam.ac.uk.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martinez Arias
keywords: Activin/Nodal and BMP signalling; Cell differentiation; Cell fate decision making; Mouse embryonic stem cell; Pluripotency; Single cell analysis; Wnt/β-catenin signalling