Journal
GENES & DEVELOPMENT
Volume 29, Issue 16, Pages 1677-1682Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.261677.115
Keywords
neurofibromin; neuroglial progenitor; AKT; MEK; Jagged1; Notch; astrocyte
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Funding
- American Brain Tumor Association
- Emily Dorfman Foundation
- National Institutes of Health [R01-NS065547-01]
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Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disordercaused byimpaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, wereport 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 differentiationis 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.
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