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Vol. 16, No. 7, pp. 846-858, April 1, 2002
1 Department of Anatomy and Cell Biology, University of
Toronto, Toronto, Ontario M5S 1A8, Canada; 2 Samuel Lunenfeld
Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5,
Canada; 3 The Amgen Institute, Ontario Cancer Institute, and
Departments of Medical Biophysics and Immunology, University of
Toronto, Toronto, Ontario M5G 2C1, Canada; 4 Molecular
Pharmacology and Biological Chemistry and Pediatrics, Northwestern
University Medical School, Chicago, Illinois 60611, USA;
5 Department of Genetics, Case Western Reserve University,
Cleveland, Ohio 44106, USA
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-J
, a key molecule in Notch signaling, by
using RBP-J
/ 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-J/ 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.
[Key Words:
Presenilin; RBP-J; embryonic stem cell; self-renewal; multipotentiality; cell cycle time]
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