Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells

S. Yamamoto, I. Yoshino, Takuya Shimazaki, M. Murohashi, R. F. Hevner, I. Lax, Hideyuki Okano, M. Shibuya, J. Schlessinger, N. Gotoh

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 FRS2α is a major mediator of signaling by means of FGFs and neurotrophins. FRS2α 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 FRS2α 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 FRS2α 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 FRS2α mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2α play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

Original languageEnglish
Pages (from-to)15983-15988
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number44
DOIs
Publication statusPublished - 2005 Nov 1

Fingerprint

Fibroblast Growth Factor 2
Stem Cells
Neural Stem Cells
Binding Sites
Neurogenesis
Lateral Ventricles
Cerebral Cortex
Multipotent Stem Cells
Ependymoglial Cells
Protein Tyrosine Phosphatases
Nerve Growth Factors
Proteins
Maintenance
Cell Proliferation
Ligands
Neurons

Keywords

  • Cell signaling
  • Docking proteins
  • Neuronal development
  • Stem cells
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells. / Yamamoto, S.; Yoshino, I.; Shimazaki, Takuya; Murohashi, M.; Hevner, R. F.; Lax, I.; Okano, Hideyuki; Shibuya, M.; Schlessinger, J.; Gotoh, N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 44, 01.11.2005, p. 15983-15988.

Research output: Contribution to journalArticle

Yamamoto, S. ; Yoshino, I. ; Shimazaki, Takuya ; Murohashi, M. ; Hevner, R. F. ; Lax, I. ; Okano, Hideyuki ; Shibuya, M. ; Schlessinger, J. ; Gotoh, N. / Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 44. pp. 15983-15988.
@article{7ac15c92e95644fdbbb9bd93e55fc129,
title = "Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells",
abstract = "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 FRS2α is a major mediator of signaling by means of FGFs and neurotrophins. FRS2α 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 FRS2α 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 FRS2α 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 FRS2α mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2α play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.",
keywords = "Cell signaling, Docking proteins, Neuronal development, Stem cells, Tyrosine phosphorylation",
author = "S. Yamamoto and I. Yoshino and Takuya Shimazaki and M. Murohashi and Hevner, {R. F.} and I. Lax and Hideyuki Okano and M. Shibuya and J. Schlessinger and N. Gotoh",
year = "2005",
month = "11",
day = "1",
doi = "10.1073/pnas.0507961102",
language = "English",
volume = "102",
pages = "15983--15988",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "44",

}

TY - JOUR

T1 - Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells

AU - Yamamoto, S.

AU - Yoshino, I.

AU - Shimazaki, Takuya

AU - Murohashi, M.

AU - Hevner, R. F.

AU - Lax, I.

AU - Okano, Hideyuki

AU - Shibuya, M.

AU - Schlessinger, J.

AU - Gotoh, N.

PY - 2005/11/1

Y1 - 2005/11/1

N2 - 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 FRS2α is a major mediator of signaling by means of FGFs and neurotrophins. FRS2α 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 FRS2α 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 FRS2α 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 FRS2α mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2α play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

AB - 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 FRS2α is a major mediator of signaling by means of FGFs and neurotrophins. FRS2α 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 FRS2α 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 FRS2α 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 FRS2α mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2α play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

KW - Cell signaling

KW - Docking proteins

KW - Neuronal development

KW - Stem cells

KW - Tyrosine phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=27644446391&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27644446391&partnerID=8YFLogxK

U2 - 10.1073/pnas.0507961102

DO - 10.1073/pnas.0507961102

M3 - Article

C2 - 16239343

AN - SCOPUS:27644446391

VL - 102

SP - 15983

EP - 15988

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 44

ER -