A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification

Abstract

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.

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

“…Cells were transferred from 2i to N2B27, and BI was applied for 25 h. We analysed cells on days 2 and 3, when Oct4‐negative/Sox1‐positive neural precursors begin to emerge 17, 33, 70. No significant effects were observed on day 2.…”

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…Additionally, EGFR is a receptor for several ligands, including Egf1 and TGFa, that acts on a plethora of signaling pathways including mitogen-activated protein kinase (MAPK) and Rac pathways, and therefore plays a crucial role in promoting proliferation, migration, differentiation, and survival. 105 Another protein that appears to play a role in neurogenic processes after HI is the fibroblast growth factor receptor 1 (Fgfr1), which promotes progenitor proliferation 106 and neuronal fate commitment in proliferating cells. 107,108 A recent study showed that ablation of the Fgfr1 gene from GFAP-expressing cells in mice leads to attenuated cell proliferation in the SVZ and decreased cortical pyramidal neuron production after HI.…”

Specific Glycosaminoglycans Modulate Neural Specification of Mouse Embryonic Stem Cells

“…ES cells respond to autocrine FGF signaling to convert to Sox1 þ NPCs [28,30]. We hypothesize that it is this step at which exogenous GAGs have their effect [25].…”

“…We then used the Ext1 À/À ES cell line to show that, although in the absence of cell surface HS ES cells fail to achieve successful neuroectodermal differentiation, this can be compensated by soluble heparin [25]. In this study, we have interrogated the specific role of HS in early signaling events during exit from self renewal into primitive ectoderm and subsequently neuroectoderm [26][27][28]. We have used the 46C ES cell line to investigate the effect of glycosaminoglycan (GAG) addition to HS-competent cells, demonstrating that GAG can be a positive or negative regulator of differentiation, dependent on size and sulfation pattern of the chains.…”