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First published online 25 May 2006
doi: 10.1242/dev.02419
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1 Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1
Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
2 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu
University, Fukuoka, Japan.
3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka
University, Osaka, Japan.
* Author for correspondence (e-mail: ygotoh{at}iam.u-tokyo.ac.jp)
Accepted 27 April 2006
The transcription factor STAT3 promotes astrocytic differentiation of
neural precursor cells (NPCs) during postnatal development of the mouse
neocortex, but little has been known of the possible role of STAT3 in the
embryonic neocortex. We now show that STAT3 is expressed in NPCs of the mouse
embryonic neocortex and that the JAK-STAT3 signaling pathway plays an
essential role in the maintenance of NPCs by fibroblast growth factor 2.
Conditional deletion of the STAT3 gene in NPCs reduced their capacity to form
neurospheres in vitro, as well as promoted neuronal differentiation both in
vitro and in vivo. Furthermore, STAT3 was found to maintain NPCs in the
undifferentiated state in a non-cell-autonomous manner. STAT3-dependent
expression of the Notch ligand Delta-like1 (DLL1) appears to account for the
non-cell-autonomous effect of STAT3 on NPC maintenance, as knockdown of DLL1
by RNA interference or inhibition of Notch activation with a 
-secretase
inhibitor abrogated the enhancement of neurosphere formation by STAT3. Our
results reveal a previously unrecognized mechanism of interaction between the
JAK-STAT3 and DLL1-Notch signaling pathways, as well as a pivotal role for
this interaction in maintenance of NPCs during early neocortical
development.
Key words: STAT3, Neural precursor cell, Neocortex, FGF2, Notch, DLL, Non-cell-autonomous
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