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J. Biol. Chem., Vol. 283, Issue 10, 6201-6208, March 7, 2008

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AICAR Induces Astroglial Differentiation of Neural Stem Cells via Activating the JAK/STAT3 Pathway Independently of AMP-activated Protein Kinase^*

Yi Zang, Li-Fang Yu, Tao Pang, Lei-Ping Fang, Xu Feng, Tie-Qiao Wen^¶, Fa-Jun Nan, Lin-Yin Feng, and Jia Li¹

From the National Center for Drug Screening and the Neurological Pharmacology Department, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203 and the ^¶School of Life Science, Shanghai University, Shanghai 200444, China

Neural stem cell differentiation and the determination of lineage decision between neuronal and glial fates have important implications in the study of developmental, pathological, and regenerative processes. Although small molecule chemicals with the ability to control neural stem cell fate are considered extremely useful tools in this field, few were reported. AICAR is an adenosine analog and extensively used to activate AMP-activated protein kinase (AMPK), a metabolic "fuel gauge" of the biological system. In the present study, we found an unrecognized astrogliogenic activity of AICAR on not only immortalized neural stem cell line C17.2 (C17.2-NSC), but also primary neural stem cells (NSCs) derived from post-natal (P0) rat hippocampus (P0-NSC) and embryonic day 14 (E14) rat embryonic cortex (E14-NSC). However, another AMPK activator, Metformin, did not alter either the C17.2-NSC or E14-NSC undifferentiated state although both Metformin and AICAR can activate the AMPK pathway in NSC. Furthermore, overexpression of dominant-negative mutants of AMPK in C17.2-NSC was unable to block the gliogenic effects of AICAR. We also found AICAR could activate the Janus kinase (JAK) STAT3 pathway in both C17.2-NSC and E14-NSC but Metformin fails. JAK inhibitor I abolished the gliogenic effects of AICAR. Taken together, these results suggest that the astroglial differentiation effect of AICAR on neural stem cells was acting independently of AMPK and that the JAK-STAT3 pathway is essential for the gliogenic effect of AICAR.

Received for publication, October 17, 2007 , and in revised form, December 11, 2007.

^* This work was supported by the National Natural Science Foundation of China (Grants 30472045 and 30623008), the Chinese Academy of Sciences (Grant KSCX2-YW-R-12), the National Basic Research Program of China (Grants 2007CB9142 and 2007CB935804), and the Shanghai Commission of Science and Technology (Grant 054319910). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: 189 Guo Shou Jing Rd., Shanghai 201203, China. Tel.: 86-21-50801313; Fax: 86-21-50801552; E-mail: TUjli{at}mail.shcnc.ac.cnUT.

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