Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways

Genes Dev. 2015 Aug 15;29(16):1677-82. doi: 10.1101/gad.261677.115. Epub 2015 Aug 13.

Abstract

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.

Keywords: AKT; Jagged1; MEK; Notch; astrocyte; neurofibromin; neuroglial progenitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Calcium-Binding Proteins / genetics
  • Cell Differentiation*
  • Cell Lineage
  • Cell Proliferation
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neural Stem Cells / cytology*
  • Neurofibromatosis 1 / genetics
  • Neurofibromatosis 1 / metabolism*
  • Neurons / cytology
  • Oncogene Protein v-akt / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptors, Notch / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transcription Factor HES-1
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Smad3 Protein
  • Transcription Factor HES-1
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins