Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways.
Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by impaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, we report that neurofibromin differentially controls neural stem cell (NSC) proliferation and multilineage differentiation through the selective use of the PI3K/AKT and RAF/MEK pathways. While PI3K/AKT governs neurofibromin-regulated NSC proliferation, multilineage differentiation is MEK-dependent. Moreover, whereas MEK-regulated multilineage differentiation requires Smad3-induced Jagged-1 expression and Notch activation, MEK/Smad3-regulated Hes1 induction is only responsible for astrocyte and neuronal differentiation. Collectively, these findings establish distinct roles for the RAS effector pathways in regulating brain NSC function.
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Yi-Hsien
YH
Chen
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Scott M
SM
Gianino
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
David H
DH
Gutmann
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051900:Smad3 Protein; D000072056:Transcription Factor HES-1; D018631:ras Proteins; C489734:Hes1 protein, mouse; C000606274:Jag1 protein, mouse
AKT; Jagged1; MEK; Notch; astrocyte; neurofibromin; neuroglial progenitor