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Molecular and Cellular Biology, July 2007, p. 4931-4937, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02435-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Potentiation of Astrogliogenesis by STAT3-Mediated Activation of Bone Morphogenetic Protein-Smad Signaling in Neural Stem Cells ^,

Shinji Fukuda,^1,2 Masahiko Abematsu,³ Hiroyuki Mori,⁴ Makoto Yanagisawa,^1,2, Tetsushi Kagawa,^1,2 Kinichi Nakashima,³ Akihiko Yoshimura,⁴ and Tetsuya Taga^1,2*

Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics,¹ The 21st Century COE Program "Cell Fate Regulation Research and Education Unit," Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811,² Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0101,³ Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan⁴

Received 30 December 2006/ Returned for modification 21 February 2007/ Accepted 10 April 2007

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.

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* Corresponding author. Mailing address: Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. Phone: 81-96-373-6610. Fax: 81-96-373-6614. E-mail: taga{at}kumamoto-u.ac.jp

Published ahead of print on 23 April 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912.

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Molecular and Cellular Biology, July 2007, p. 4931-4937, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02435-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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