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PMID: 11937492 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells.

Genes & development ·Vol. 16 ·No. 7 ·2002-04-01 ·Pages 846-58

Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D

Abstract

Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jkappa, a key molecule in Notch signaling, by using RBP-Jkappa(-/-) embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains of RBP-Jkappa(-/-) or Notch1(-/-) mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1(+/-) adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.

MeSH Terms
Animals Brain/metabolism Bromodeoxyuridine/pharmacology Cell Cycle Cell Differentiation Central Nervous System/embryology,metabolism Immunohistochemistry Membrane Proteins/metabolism Mice Microscopy, Fluorescence Mutation Neurons/metabolism Presenilin-1 Prosencephalon/metabolism Protein Binding Receptor, Notch1 Receptors, Cell Surface Receptors, Notch Retroviridae/genetics Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Time Factors Transcription Factors
Chemicals
Membrane Proteins Notch1 protein, mouse Presenilin-1 Receptor, Notch1 Receptors, Cell Surface Receptors, Notch Transcription Factors Bromodeoxyuridine
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Hitoshi Seiji
Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. shitoshi-tky@umin.ac.jp
Alexson Tania
Tropepe Vincent
Donoviel Dorit
Elia Andrew J
Nye Jeffrey S
Conlon Ronald A
Mak Tak W
Bernstein Alan
van der Kooy Derek
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.975202
Email
shitoshi-tky@umin.ac.jp
Published
2002-04-01
Pages
846-58
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC186324
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.975202 PMC Full Text View journal details
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