FRS2α regulates Erk levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells.
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.
Sato
Takuya
T
Division of Systems Biomedical Technology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Shimazaki
Takuya
T
Naka
Hayato
H
Fukami
Shin-Ichi
S
Satoh
Yasushi
Y
Okano
Hideyuki
H
Lax
Irit
I
Schlessinger
Joseph
J
Gotoh
Noriko
N
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology*; D013687:Telencephalon / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*; D013997:Time Factors; D000072056:Transcription Factor HES-1; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D051380:GRB2 Adaptor Protein; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D000072056:Transcription Factor HES-1; C488187:FRS2alpha protein, mouse; C495949:Grb2 protein, mouse; C489734:Hes1 protein, mouse