FRS2α Regulates Erk Levels to Control a Self-Renewal Target Hes1 and Proliferation of FGF-Responsive Neural Stem/Progenitor Cells§

Authors


  • Author contributions: T. Sato: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; T. Shimazaki: conception and design, provision of study material or patients, final approval of manuscript; H. N.: provision of study material or patients; S.-I.F.: provision of study material or patients; Y.S.: provision of study material or patients; H.O.: provision of study material or patients, final approval of manuscript; I.L.: final approval of manuscript; J.S.: final approval of manuscript; N.G.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS July 22, 2010.

Abstract

Fibroblast growth factor (FGF) is among the most common growth factors used in cultures to maintain self-renewal and proliferative capabilities of a variety of stem cells, including neural stem cells (NSCs). However, the molecular mechanisms underlying the control by FGF have remained elusive. Studies on mutant mice of FGF receptor substrate 2α (FRS2α), a central mediator for FGF signaling, combined with FRS2α knockdown or gain-of-function experiments, allowed us to dissect the role of FGF signaling for the self-renewal and proliferation of NSCs and to provide novel molecular mechanisms for them. We identified Hes1 as a novel self-renewal target of FGF-signaling. Quantitatively different levels of Erk activation mediated by FRS2α may regulate self-renewal of NSCs and proliferation of neural stem/progenitor cells (NSPCs); low levels of Erk activation are sufficient for the former, however, higher levels are required for maximum activity of the latter. Thus, FRS2α fine-tunes the FGF-signaling to control qualitatively different biological activities, self-renewal at least partly through Hes1 versus proliferation of NSPCs. STEM CELLS 2010; 28:1661–1673.

Ancillary