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

Yamamoto, Shin Ichi; Yoshino, Ichiro; Shimazaki, Takuya; Murohashi, Michiko; Hevner, Robert F.; Lax, Irit; Okano, Hideyuki; Shibuya, Masabumi; Schlessinger, Joseph; Gotoh, Noriko

doi:10.1073/pnas.0507961102

Cited by 63 publications

(59 citation statements)

References 44 publications

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“…bFGF activates the Erk pathway mainly by promoting the association of FRS2a (fibroblast receptor substrate 2a) with Shp2 (14). FRS2a knockin mice (Frs2a 2F/2F ) lacking the two Shp2-docking sites display severely impaired cortical development and neurogenesis, due in part to defects in intermediate progenitor cells (38). Interestingly, Frs2␣ 2F/2F NSCs form smaller neurospheres but can self-renew in vitro, in contrast to our observation of Shp2-deficient NSCs' failure in self-renewal in vitro.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality

Zhang

Hagihara

et al. 2007

Molecular and Cellular Biology

118

126

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The intracellular signaling controlling neural stem/progenitor cell (NSC) self-renewal and neuronal/glial differentiation is not fully understood. We show here that Shp2, an introcellular tyrosine phosphatase with two SH2 domains, plays a critical role in NSC activities. Conditional deletion of Shp2 in neural progenitor cells mediated by Nestin-Cre resulted in early postnatal lethality, impaired corticogenesis, and reduced proliferation of progenitor cells in the ventricular zone. In vitro analyses suggest that Shp2 mediates basic fibroblast growth factor signals in stimulating self-renewing proliferation of NSCs, partly through control of Bmi-1 expression. Furthermore, Shp2 regulates cell fate decisions, by promoting neurogenesis while suppressing astrogliogenesis, through reciprocal regulation of the Erk and Stat3 signaling pathways. Together, these results identify Shp2 as a critical signaling molecule in coordinated regulation of progenitor cell proliferation and neuronal/astroglial cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality

Zhang

Hagihara

et al. 2007

Molecular and Cellular Biology

118

126

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“…The mechanisms used to mediate signals between ErbB receptors and Shp2 was not studied here. In the case of other tyrosine kinase receptors, Shp2 binds directly to the receptors, e.g., the PDGFR, or indirectly via adaptor proteins, for instance FRS2␣ or Gab1 that are recruited to the FGF or Met receptors, respectively (28,30,57,58). Krox20/Egr2 is essential for myelination and myelin gene expression (59).…”

Section: Discussionmentioning

confidence: 99%

The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development

Grossmann

Wende²,

Paul

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The nonreceptor tyrosine phosphatase Shp2 (PTPN11) has been implicated in tyrosine kinase, cytokine, and integrin receptor signaling. We show here that conditional mutation of Shp2 in neural crest cells and in myelinating Schwann cells resulted in deficits in glial development that are remarkably similar to those observed in mice mutant for Neuregulin-1 (Nrg1) or the Nrg1 receptors, ErbB2 and ErbB3. In cultured Shp2 mutant Schwann cells, Nrg1-evoked cellular responses like proliferation and migration were virtually abolished, and Nrg1-dependent intracellular signaling was altered. Pharmacological inhibition of Src family kinases mimicked all cellular and biochemical effects of the Shp2 mutation, implicating Src as a primary Shp2 target during Nrg1 signaling. Together, our genetic and biochemical analyses demonstrate that Shp2 is an essential component in the transduction of Nrg1/ErbB signals.ErbB2/3 ͉ myelination ͉ tyrosine kinase receptors

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“…Growth factor receptors activate the PI3K (Pik3r1 -Mouse Genome Informatics) pathway, which induces phosphorylation and stabilization of N-myc protein (Kenney et al, 2004). In addition, Egfr as well as Frs2, an adaptor of Fgfr/Egfr, have been shown to regulate the production of basal progenitors (Yamamoto et al, 2005). The RNA-binding protein HuC/D is another candidate that could regulate N-myc function in basal progenitors, as it binds to and stabilizes N-myc mRNA and is localized in the SVZ (Lazarova et al, 1999;Miyata et al, 2004).…”

Section: Research Articlementioning

confidence: 99%

Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex

et al. 2010

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SUMMARYBasal progenitors (also called non-surface dividing or intermediate progenitors) have been proposed to regulate the number of neurons during neocortical development through expanding cells committed to a neuronal fate, although the signals that govern this population have remained largely unknown. Here, we show that N-myc mediates the functions of Wnt signaling in promoting neuronal fate commitment and proliferation of neural precursor cells in vitro. Wnt signaling and N-myc also contribute to the production of basal progenitors in vivo. Expression of a stabilized form of -catenin, a component of the Wnt signaling pathway, or of N-myc increased the numbers of neocortical basal progenitors, whereas conditional deletion of the N-myc gene reduced these and, as a likely consequence, the number of neocortical neurons. These results reveal that Wnt signaling via N-myc is crucial for the control of neuron number in the developing neocortex.

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

Abstract: cell signaling ͉ docking proteins ͉ neuronal development ͉ stem cells ͉ tyrosine phosphorylation

Cited by 63 publications

References 44 publications

Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality

Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality

The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development

Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex

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