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Molecular and Cellular Biology, January 2004, p. 280-293, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.280-293.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ASK1 Inhibits Astroglial Development via p38 Mitogen-Activated Protein Kinase and Promotes Neuronal Differentiation in Adult Hippocampus-Derived Progenitor Cells

Roland Faigle,* Anke Brederlau, Muna Elmi, Yvonne Arvidsson, Tatsuo S. Hamazaki,{dagger} Hidetaka Uramoto, and Keiko Funa*

Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Göteborg University, Gothenburg, Sweden

Received 24 March 2003/ Returned for modification 25 June 2003/ Accepted 1 October 2003

The mechanisms controlling differentiation and lineage specification of neural stem cells are still poorly understood, and many of the molecules involved in this process and their specific functions are yet unknown. We investigated the effect of apoptosis signal-regulating kinase 1 (ASK1) on neural stem cells by infecting adult hippocampus-derived rat progenitors with an adenovirus encoding the constitutively active form of ASK1. Following ASK1 overexpression, a significantly larger number of cells differentiated into neurons and a substantial increase in Mash1 transcription was observed. Moreover, a marked depletion of glial cells was observed, persisting even after additional treatment of ASK1-infected cultures with potent glia inducers such as leukemia inhibitory factor and bone morphogenetic protein. Analysis of the promoter for glial fibrillary acidic protein revealed that ASK1 acts as a potent inhibitor of glial-specific gene transcription. However, the signal transducers and activators of transcription 3 (STAT3)-binding site in the promoter was dispensable, while the activation of p38 mitogen-activated protein kinase was crucial for this effect, suggesting the presence of a novel mechanism for the inhibition of glial differentiation.

* Corresponding author. Mailing address: Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Göteborg University, Box 420, SE-40530, Gothenburg, Sweden. Phone: 46 31 773 3151. Fax: 46 31 773 3360. E-mail: keiko.funa{at}anatcell.gu.se.

{dagger} Present address: Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.

Molecular and Cellular Biology, January 2004, p. 280-293, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.280-293.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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