Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells.

Mammalian corticogenesis occurs through a complex process that includes neurogenesis, in which neural progenitor cells proliferate, differentiate, and migrate. It has been reported recently that neurogenesis occurs in the subventricular zone (SVZ), a region previously thought to be the primary site of gliogenesis. It has been recognized that in the SVZ, intermediate progenitor cells, derived from radial glial cells that are multipotent neural stem cells, produce only neurons. However, the molecular mechanisms underlying the regulation of neural stem cells and intermediate progenitor cells as well as their contribution to overall corticogenesis remain unknown. The docking protein FRS2alpha is a major mediator of signaling by means of FGFs and neurotrophins. FRS2alpha mediates many of its pleiotropic cellular responses by recruiting the adaptor protein Grb2 and the protein tyrosine phosphatase Shp2 upon ligand stimulation. Here, we report that targeted disruption of Shp2-binding sites in FRS2alpha leads to severe impairment in cerebral cortex development in mutant mice. The defect in corticogenesis appears to be due at least in part to abnormalities in intermediate progenitor cells. Genetic evidence is provided that FRS2alpha plays critical roles in the maintenance of intermediate progenitor cells and in neurogenesis in the cerebral cortex. Moreover, FGF2-responsive neurospheres, which are cell aggregates derived from neural stem/progenitor cells (NSPCs), from FRS2alpha mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2alpha play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

[1]  K. Manova,et al.  The Docking Protein FRS2α Is an Essential Component of Multiple Fibroblast Growth Factor Responses during Early Mouse Development , 2005, Molecular and Cellular Biology.

[2]  C. Englund,et al.  Pax6, Tbr2, and Tbr1 Are Expressed Sequentially by Radial Glia, Intermediate Progenitor Cells, and Postmitotic Neurons in Developing Neocortex , 2005, The Journal of Neuroscience.

[3]  M. Shibuya,et al.  Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  R. Bodmer,et al.  Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons. , 2004, Cerebral cortex.

[5]  M. Shibuya,et al.  SNT-2 interacts with ERK2 and negatively regulates ERK2 signaling in response to EGF stimulation. , 2004, Biochemical and biophysical research communications.

[6]  K. Unsicker,et al.  TrkB regulates neocortex formation through the Shc/PLCγ‐mediated control of neuronal migration , 2004, The EMBO journal.

[7]  Masako Kawano,et al.  Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells , 2004, Development.

[8]  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.

[9]  G. Fishell,et al.  Radial Glia Serve as Neuronal Progenitors in All Regions of the Central Nervous System , 2004, Neuron.

[10]  Winfried Denk,et al.  Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Kriegstein,et al.  Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases , 2004, Nature Neuroscience.

[12]  Bernhard Reuss,et al.  Fibroblast growth factors and their receptors in the central nervous system , 2003, Cell and Tissue Research.

[13]  V. Gallo,et al.  Postnatal NG2 proteoglycan–expressing progenitor cells are intrinsically multipotent and generate functional neurons , 2003, The Journal of cell biology.

[14]  M. Götz,et al.  Neuronal or Glial Progeny Regional Differences in Radial Glia Fate , 2003, Neuron.

[15]  G. Fishell,et al.  Neurons from radial glia: the consequences of asymmetric inheritance , 2003, Current Opinion in Neurobiology.

[16]  H. Okano,et al.  RNA-binding protein Musashi family: Roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  I. Lax,et al.  The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. , 2002, Molecular cell.

[18]  H. Okano.  Stem cell biology of the central nervous system , 2002, Journal of neuroscience research.

[19]  M. Hatten,et al.  New Directions in Neuronal Migration , 2002, Science.

[20]  P. Rakic,et al.  Origin of GABAergic neurons in the human neocortex , 2002, Nature.

[21]  S. Morrison.  Neuronal potential and lineage determination by neural stem cells. , 2001, Current opinion in cell biology.

[22]  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.

[23]  V. Tarabykin,et al.  Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. , 2001, Development.

[24]  I. Lax,et al.  Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Arturo Alvarez-Buylla,et al.  A unified hypothesis on the lineage of neural stem cells , 2001, Nature Reviews Neuroscience.

[26]  J. Leckman,et al.  Basic Fibroblast Growth Factor (Fgf2) Is Necessary for Cell Proliferation and Neurogenesis in the Developing Cerebral Cortex , 2000, The Journal of Neuroscience.

[27]  John G. Parnavelas,et al.  The origin and migration of cortical neurones: new vistas , 2000, Trends in Neurosciences.

[28]  H. Okano,et al.  Musashi1: An Evolutionally Conserved Marker for CNS Progenitor Cells Including Neural Stem Cells , 2000, Developmental Neuroscience.

[29]  D. van der Kooy,et al.  Separate Proliferation Kinetics of Fibroblast Growth Factor-Responsive and Epidermal Growth Factor-Responsive Neural Stem Cells within the Embryonic Forebrain Germinal Zone , 2000, The Journal of Neuroscience.

[30]  S. Weiss,et al.  The bHLH Gene Hes1 as a Repressor of the Neuronal Commitment of CNS Stem Cells , 2000, The Journal of Neuroscience.

[31]  M. Rao.  Multipotent and restricted precursors in the central nervous system , 1999, The Anatomical record.

[32]  D. van der Kooy,et al.  Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. , 1999, Developmental biology.

[33]  T. Doetschman,et al.  Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis , 1999, Nature Neuroscience.

[34]  R. McKay,et al.  Regulation of neurogenesis by growth factors and neurotransmitters. , 1998, Journal of neurobiology.

[35]  S. Tsang,et al.  Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Bar-Sagi,et al.  A Lipid-Anchored Grb2-Binding Protein That Links FGF-Receptor Activation to the Ras/MAPK Signaling Pathway , 1997, Cell.

[37]  C. Henderson.  Role of neurotrophic factors in neuronal development , 1996, Current Opinion in Neurobiology.

[38]  Maria B. Luskin,et al.  Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone , 1993, Neuron.

[39]  N. Copeland,et al.  trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. , 1993, Development.