The role of FGF/Erk signaling in pluripotent cells

Abstract

SummaryFibroblast growth factor (FGF) signaling controls fundamental processes such as proliferation, differentiation and migration throughout mammalian development. Here we discuss recent discoveries that implicate FGF/Erk signaling in the control of pluripotency and lineage specification in several different stem cell states, including the separation of pluripotent epiblast and primitive endoderm in the blastocyst, the lineage priming of embryonic stem (ES) cells, and in the stabilization of the metastable state of mouse epiblast and human ES cells. Understanding how extrinsic signals such as FGF regulate different stem cell states will be crucial to harvest the clinical promise of induced pluripotent and embryo-derived stem cells. Key words: FGF signaling, Stem cells, Embryonic development IntroductionFibroblast growth factors (FGFs) and their receptor tyrosine kinases control a multitude of developmental processes, including proliferation, survival, migration and differentiation. In this review, we discuss recently emerging evidence that FGF signaling plays an important role in regulating pluripotency and lineage segregation in both the early mouse embryo and in pluripotent mammalian stem cells. Although mouse and human embryonic stem (ES) cells are both derived from the pluripotent inner cell mass (ICM) cells of the pre-implantation blastocyst, they exhibit fundamental differences, whereby mouse ES cells appear to represent a developmentally more 'naïve' pre-implantation state and human ES cells a 'primed' post-implantation state ), similar to mouse epiblast-derived stem cells (EpiSCs) (Brons et al., 2007;Tesar et al., 2007). Intriguing recent findings suggest an important role for FGF/extracellular signal-regulated kinase (Erk) signaling in promoting the transition from a naïve to a primed state and in preventing primed cells from reverting back to a naïve state, in effect stabilizing the primed cell state (Hanna et al., 2009;Li et al., 2009;Greber et al., 2010;Hanna et al., 2010). Modulating FGF/Erk signaling might therefore facilitate the conversion of conventional human ES cells into a more naïve and mouse-like state. The existence of multiple and possibly interconvertible pluripotent stem cell states controlled by the extrinsic signaling environment could have significant implications not only for early developmental biology, but also for the field of reprogramming and induced pluripotency.FGF signaling FGF signaling is activated by a ligand-receptor interaction that results in the autophosphorylation of tyrosine residues in the intracellular region of an FGF receptor (FGFR). The signal is further relayed through four distinct pathways: the Janus kinase/signal transducer and activator of transcription (Jak/Stat), phosphoinositide phospholipase C (PLCg), phosphatidylinositol 3-kinase (PI3K) and Erk pathways (Dailey et al., 2005) (Fig. 1). The formation of a complex between FGFR, fibroblast growth factor receptor substrate 2 (Frs2a), Src homology region 2 domaincontaining phosphatase 2 (Shp2; also known ...

Bifurcation analysis of single-cell gene expression data reveals epigenetic landscape

“…Many known important developmental regulators (red labels in Fig. 2B) had large weights that were consistent with their functional role (37)(38)(39). For example, at the 32-cell stage, the bottom-ranked transcription factors were Id2 (inhibitor of DNA binding 2) and Tcfap2a and the top-ranked transcription factors Sox2 [SRY (sex determining region Y)-box 2] and Snai1.…”

Specification of functional neurons and glia from human pluripotent stem cells

“…BMP signaling, which maintains the pluripotency of mESCs, promote the hESC to differentiate, preferably into trophblast (Xu et al, 2002). In contrast, the FGF2, which is routinely used in hESC culture, initiate the differentiation of mESCs (Lanner and Rossant, 2010). The similar scenario seems exist during the neural differentiation from ESCs as well.…”

Calcium signaling in human pluripotent stem cells

“…3). The balanced, moderate level of activated ERK sustains the pluripotent state [51,57], while a strong reduction of PI3K activity causes elevated ERK activity followed by differentiation of PSCs (as shown in mouse studies [58,59]). …”