Activation of MAPK/PI3K/SMAD pathways by TGF-β(1) controls differentiation of radial glia into astrocytes in vitro.
The major neural stem cell population in the developing cerebral cortex is the radial glia cells, which generate neurons and glial cells. The mechanisms that modulate the maintenance of the radial glia stem cell phenotype, or its differentiation, are not completely elucidated. We previously demonstrated that transforming growth factor-β(1) (TGF-β(1)) promotes radial glia differentiation into astrocytes in vitro [Glia 2007;55:1023-1033]. Here we investigated the intracellular signaling pathways involved in the TGF-β(1)-induced radial glia fate commitment. We demonstrate that the mechanisms underlying the TGF-β(1) effect on radial glia cell differentiation or progenitor potential maintenance diverge. Whereas radial glia differentiation into astrocytes is mediated by the activation of the MAPK signaling pathway, neurogenesis is modulated by different levels of PI3K and SMAD2/3 activity. Our work demonstrates that radial glia cells are a heterogeneous population and a potential target of TGF-β(1), and suggests that its effect on radial glia fate commitment is mediated by the recruitment of a complex multipathway mechanism that controls astrocyte and neuronal generation in the developing cerebral cortex.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Joice
J
Stipursky
Daniel
D
Francis
Flávia Carvalho Alcantara
FC
Gomes
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development; D004149:Dioxoles / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
D001549:Benzamides; D004149:Dioxoles; D005419:Flavonoids; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one