The role of FGF/Erk signaling in pluripotent cells

Fibroblast 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.

[1]  J. Rossant,et al.  Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts , 2005, Development.

[2]  Hitoshi Niwa,et al.  A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells , 2009, Nature.

[3]  C. Lim,et al.  Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells , 2009, PLoS biology.

[4]  Kazuki Kurimoto,et al.  An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis , 2006, Nucleic acids research.

[5]  M. Surani,et al.  Generation of stella‐GFP transgenic mice: A novel tool to study germ cell development , 2006, Genesis.

[6]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[7]  C. Hsieh,et al.  Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts , 2008, Cell.

[8]  H. Schöler,et al.  Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells. , 2010, Cell stem cell.

[9]  N. Nakatsuji,et al.  STAT3 Is Dispensable for Maintenance of Self‐Renewal in Nonhuman Primate Embryonic Stem Cells , 2004, Stem cells.

[10]  J. Nichols,et al.  Klf4 reverts developmentally programmed restriction of ground state pluripotency , 2009, Development.

[11]  Anna-Katerina Hadjantonakis,et al.  Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst , 2008, Development.

[12]  B. Doble,et al.  The ground state of embryonic stem cell self-renewal , 2008, Nature.

[13]  Marios P. Stavridis,et al.  Development and Stem Cells Research Article , 2022 .

[14]  I. Lax,et al.  FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial‐temporal patterns of expression of their transcripts , 2004, FEBS letters.

[15]  J. Nichols,et al.  Nanog safeguards pluripotency and mediates germline development , 2007, Nature.

[16]  F. Gage,et al.  Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification , 2006, Nature Clinical Practice Cardiovascular Medicine.

[17]  Naoya Nakai,et al.  Essential role for ERK2 mitogen‐activated protein kinase in placental development , 2003, Genes to cells : devoted to molecular & cellular mechanisms.

[18]  N. Terada,et al.  A Heterogeneous Expression Pattern for Nanog in Embryonic Stem Cells , 2007, Stem cells.

[19]  Austin G Smith,et al.  Capture of Authentic Embryonic Stem Cells from Rat Blastocysts , 2008, Cell.

[20]  L. Brill,et al.  Phosphoproteomic analysis of human embryonic stem cells. , 2009, Cell stem cell.

[21]  G. Daley,et al.  Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos , 2008, Nature Genetics.

[22]  Janet Rossant,et al.  FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst , 2010, Development.

[23]  G. Martin,et al.  An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination , 1998, Nature Genetics.

[24]  C. Deng,et al.  FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. , 1998, Development.

[25]  V. Papaioannou,et al.  Requirement of FGF-4 for postimplantation mouse development , 1995, Science.

[26]  Janet Rossant,et al.  Direct Neural Fate Specification from Embryonic Stem Cells A Primitive Mammalian Neural Stem Cell Stage Acquired through a Default Mechanism , 2001, Neuron.

[27]  Austin G Smith,et al.  Essential Alterations of Heparan Sulfate During the Differentiation of Embryonic Stem Cells to Sox1‐Enhanced Green Fluorescent Protein‐Expressing Neural Progenitor Cells , 2007, Stem cells.

[28]  J. Rossant,et al.  fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. , 1994, Genes & development.

[29]  Marios P. Stavridis,et al.  A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification , 2007, Development.

[30]  D. Ambrosetti,et al.  Mechanisms underlying differential responses to FGF signaling. , 2005, Cytokine & growth factor reviews.

[31]  H. Niwa,et al.  Identification and characterization of subpopulations in undifferentiated ES cell culture , 2008, Development.

[32]  J. Pouysségur,et al.  Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. , 1999, Science.

[33]  J. Nichols,et al.  Naive and primed pluripotent states. , 2009, Cell stem cell.

[34]  Sean C. Bendall,et al.  IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro , 2007, Nature.

[35]  C. Lengner,et al.  Metastable pluripotent states in NOD-mouse-derived ESCs. , 2009, Cell stem cell.

[36]  R. Pedersen,et al.  Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells , 2005, Journal of Cell Science.

[37]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[38]  J. Rossant,et al.  Heparan Sulfation–Dependent Fibroblast Growth Factor Signaling Maintains Embryonic Stem Cells Primed for Differentiation in a Heterogeneous State , 2009, Stem cells.

[39]  M. Trotter,et al.  Derivation of pluripotent epiblast stem cells from mammalian embryos , 2007, Nature.

[40]  H. Lehrach,et al.  Fibroblast Growth Factor 2 Modulates Transforming Growth Factor β Signaling in Mouse Embryonic Fibroblasts and Human ESCs (hESCs) to Support hESC Self‐Renewal , 2007, Stem cells.

[41]  S. Mansour.  Targeted disruption of int‐2 (fgf‐3) causes developmental defects in the tail and inner ear , 1994, Molecular reproduction and development.

[42]  E. Kroon,et al.  Efficient differentiation of human embryonic stem cells to definitive endoderm , 2005, Nature Biotechnology.

[43]  Sheila M. Thomas,et al.  An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. , 2006, Developmental cell.

[44]  H. Deng,et al.  MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal. , 2007, Differentiation; research in biological diversity.

[45]  G. Martin,et al.  FGF5 as a regulator of the hair growth cycle: Evidence from targeted and spontaneous mutations , 1994, Cell.

[46]  F. Tang,et al.  Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. , 2008, Cell stem cell.

[47]  Mary Anne Wheeler,et al.  Stem , 1985 .

[48]  J. Heath,et al.  Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[49]  N. Itoh,et al.  Evolution of the Fgf and Fgfr gene families. , 2004, Trends in genetics : TIG.

[50]  J. Rossant.  Stem Cells and Early Lineage Development , 2008, Cell.

[51]  J. Rossant,et al.  Investigation of the fate of 4-5 day post-coitum mouse inner cell mass cells by blastocyst injection. , 1979, Journal of embryology and experimental morphology.

[52]  Tony Pawson,et al.  Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. , 2006, Developmental cell.

[53]  Sheng Ding,et al.  Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. , 2009, Cell stem cell.

[54]  G. Martin,et al.  mRNA localization studies suggest that murine FGF-5 plays a role in gastrulation. , 1991, Development.

[55]  P. Leder,et al.  Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth , 1996, Cell.

[56]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[57]  T. Pawson,et al.  Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp‐2 , 1997, The EMBO journal.

[58]  Ge Lin,et al.  Inhibition of Caspase-mediated Anoikis Is Critical for Basic Fibroblast Growth Factor-sustained Culture of Human Pluripotent Stem Cells* , 2009, The Journal of Biological Chemistry.

[59]  N. Corbi,et al.  Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. , 1995, Genes & development.

[60]  M. Capecchi,et al.  Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. , 1997, Developmental biology.

[61]  J. Rossant,et al.  Promotion of trophoblast stem cell proliferation by FGF4. , 1998, Science.

[62]  Donald Metcalf,et al.  Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells , 1988, Nature.

[63]  P. Greengard,et al.  Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor , 2004, Nature Medicine.

[64]  A. Trounson,et al.  Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro , 2000, Nature Biotechnology.

[65]  F. Tang,et al.  Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells , 2009, Nature.

[66]  J. Nichols,et al.  Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. , 2009, Cell stem cell.

[67]  S. Meloche,et al.  An essential function of the mitogen‐activated protein kinase Erk2 in mouse trophoblast development , 2003, EMBO reports.

[68]  R. McKay,et al.  New cell lines from mouse epiblast share defining features with human embryonic stem cells , 2007, Nature.

[69]  J. Nichols,et al.  Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo , 2009, Development.

[70]  Wanguo Wei,et al.  Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules , 2010, Proceedings of the National Academy of Sciences.

[71]  Tony Pawson,et al.  Mammalian Grb2 Regulates Multiple Steps in Embryonic Development and Malignant Transformation , 1998, Cell.

[72]  Alexei A. Sharov,et al.  Functional Heterogeneity of Embryonic Stem Cells Revealed through Translational Amplification of an Early Endodermal Transcript , 2010, PLoS biology.

[73]  J. Thomson,et al.  BMP4 initiates human embryonic stem cell differentiation to trophoblast , 2002, Nature Biotechnology.

[74]  Austin G Smith,et al.  FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment , 2007, Development.

[75]  J. Rossant,et al.  Fibroblast growth factors in mammalian development. , 1995, Current opinion in genetics & development.

[76]  C. Lengner,et al.  Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs , 2010, Proceedings of the National Academy of Sciences.

[77]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[78]  Mikael Huss,et al.  Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. , 2010, Developmental cell.

[79]  I. Lax,et al.  Critical role for the docking-protein FRS2α in FGF receptor-mediated signal transduction pathways , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Samantha A. Morris,et al.  Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo , 2010, Proceedings of the National Academy of Sciences.

[81]  R. Zeller,et al.  Impaired cerebral cortex development and blood pressure regulation in FGF‐2‐deficient mice , 1998, The EMBO journal.

[82]  P. Leder,et al.  Murine FGFR-1 is required for early postimplantation growth and axial organization. , 1994, Genes & development.

[83]  John K. Heath,et al.  Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides , 1988, Nature.

[84]  C. Mummery,et al.  Phosphorylation dynamics during early differentiation of human embryonic stem cells. , 2009, Cell stem cell.

[85]  Nobuyuki Itoh,et al.  Fibroblast growth factors , 2001, Genome Biology.

[86]  C. Peterson,et al.  Stem cell states, fates, and the rules of attraction. , 2009, Cell stem cell.

[87]  Š. Pospíšilová,et al.  A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells , 2009, Stem cells.

[88]  Kit T. Rodolfa,et al.  Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. , 2010, Genes & development.

[89]  G. Martin,et al.  Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[90]  J. C. Chisholm,et al.  Cytokeratin filament assembly in the preimplantation mouse embryo. , 1987, Development.

[91]  J. Nichols,et al.  BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3 , 2003, Cell.

[92]  J. Nichols,et al.  Validated germline-competent embryonic stem cell lines from nonobese diabetic mice , 2009, Nature Medicine.

[93]  Gary W. Harding,et al.  Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 , 1996, Nature Genetics.