Regulation of neural stem/progenitor cell maintenance by PI3K and mTOR.
Control of stem cell state and differentiation of neural stem/progenitor cells is essential for proper development of the nervous system. EGF and FGF2 play important roles in the control of neural stem/progenitor cells, but the underlying mechanism still remains unclear. Here we show, using in vitro primary cultures of mouse neural stem/progenitor cells, that both PI3K and mTOR are activated by EGF/FGF2 but that inhibiting the activation of either PI3K or mTOR alone results in only reduced proliferation of neural stem/progenitor cells without affecting their stem cell state, namely, the capacity to self-renew. However, significantly, concurrent inhibition of PI3K and mTOR promoted exit from the stem cell state together with astrocytic differentiation of neural stem/progenitor cells. These findings suggest that PI3K and mTOR are involved in the EGF/FGF2-mediated maintenance of neural stem/progenitor cells and that they may act in parallel and independent pathways, complementing and backing up each other to maintain the stem cell state.
Sato
Atsushi
A
Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 lida-nishi, Yamagata 990-9585, Japan; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Sunayama
Jun
J
Matsuda
Ken-ichiro
K
Tachibana
Ken
K
Sakurada
Kaori
K
Tomiyama
Arata
A
Kayama
Takamasa
T
Kitanaka
Chifumi
C
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016548:Prosencephalon / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014404:Tubulin / Q000378:metabolism
D004815:Epidermal Growth Factor; D016222:Fibroblast Growth Factor 2; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D055748:SOXB1 Transcription Factors; D058570:TOR Serine-Threonine Kinases; D014404:Tubulin; C527783:Sox2 protein, mouse; C462941:beta3 tubulin, mouse; C546843:mTOR protein, mouse