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

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.

• Authors: Yi-Hsien Chen, Scott M Gianino, David H Gutmann
• Journal: Genes & development (Genes Dev) Vol. 29 Issue 16 Pg. 1677-82 (Aug 15 2015) ISSN: 1549-5477 [Electronic] United States
• PMID: 26272820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Chen et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• 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

Topics

• 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, metabolism)
• Neurons (cytology)
• Oncogene Protein v-akt (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Receptors, Notch (metabolism)
• Serrate-Jagged Proteins
• Signal Transduction
• Smad3 Protein (genetics, metabolism)
• Transcription Factor HES-1
• ras Proteins (genetics, metabolism)