A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification.
Neural tissue formation is induced by growth factors that activate networks of signal transduction cascades that ultimately lead to the expression of early neural genes, including transcription factors of the SoxB family. Here, we report that fibroblast growth factor (FGF)-induced Erk1/2 (Mapk3 and Mapk1, respectively) mitogen-activated protein kinase (MAPK), but not phosphatidylinositol 3'-OH kinase (PI3K, Pik3r1), signalling is required for neural specification in mouse embryonic stem (ES) cells and in the chick embryo. Further, blocking Erk1/2 inhibits the onset of key SoxB genes in both mouse ES cells (Sox1) and chick embryos (Sox2 and Sox3) and, in both contexts, Erk1/2 signalling is required during only a narrow time window, as neural specification takes place. In the absence of Erk1/2 signalling, differentiation of ES cells stalls following Fgf5 upregulation. Using differentiating ES cells as a model for neural specification, we demonstrate that sustained Erk1/2 activation controls the transition from an Fgf5-positive, primitive ectoderm-like cell state to a neural progenitor cell state without attenuating bone morphogenetic protein (BMP) signalling and we also define the minimum period of Erk1/2 activity required to mediate this key developmental step. Together, these findings identify a conserved, specific and stage-dependent requirement for Erk1/2 signalling downstream of FGF-induced neural specification in higher vertebrates and provide insight into the signalling dynamics governing this process.
Division of Cell and Developmental Biology, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Marios P
MP
Stavridis
J Simon
JS
Lunn
Barry J
BJ
Collins
Kate G
KG
Storey
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D002478:Cells, Cultured; D002642:Chick Embryo; D004475:Ectoderm / Q000166:cytology; D005346:Fibroblast Growth Factors / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D015398:Signal Transduction; D013997:Time Factors
D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3