Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells.
Astrocytes play important roles in brain development and injury response. Transcription factors STAT3 and Smad1, activated by leukemia inhibitory factor (LIF) and bone morphogenetic protein 2 (BMP2), respectively, form a complex with the coactivator p300 to synergistically induce astrocytes from neuroepithelial cells (NECs) (K. Nakashima, M. Yanagisawa, H. Arakawa, N. Kimura, T. Hisatsune, M. Kawabata, K. Miyazono, and T. Taga, Science 284:479-482, 1999). However, the mechanisms that govern astrogliogenesis during the determination of the fate of neural stem cells remain elusive. Here we found that LIF induces expression of BMP2 via STAT3 activation and leads to the consequent activation of Smad1 to efficiently promote astrogliogenic differentiation of NECs. The BMP antagonist Noggin abrogated LIF-induced Smad1 activation and astrogliogenesis by inhibiting BMPs produced by NECs. NECs deficient in suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3, readily differentiated into astrocytes upon activation by LIF not only due to sustained activation of STAT3 but also because of the consequent activation of Smad1. Our study suggests a novel LIF-triggered positive regulatory loop that enhances astrogliogenesis.
Fukuda
Shinji
S
Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Abematsu
Masahiko
M
Mori
Hiroyuki
H
Yanagisawa
Makoto
M
Kagawa
Tetsushi
T
Nakashima
Kinichi
K
Yoshimura
Akihiko
A
Taga
Tetsuya
T
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D053612:Janus Kinases / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D046569:Neuroepithelial Cells / Q000166:cytology* / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; D051898:Smad1 Protein; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D053612:Janus Kinases