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Molecular and Cellular Biology, June 2007, p. 4293-4305, Vol. 27, No. 12
0270-7306/07/$08.00+0 doi:10.1128/MCB.00031-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Bcl-XL/Bax Proteins Direct the Fate of Embryonic Cortical Precursor Cells
,
Mi-Yoon Chang,1,2,
Woong Sun,4
Wataru Ochiai,5
Kinichi Nakashima,6
Soo-Young Kim,4
Chang-Hwan Park,2,7
Jin Sun Kang,2,7
Jae-Won Shim,1,2,3
A-Young Jo,1,2,3
Chun-Sik Kang,1
Yong-Sung Lee,1,2,3
Jae-Sang Kim,8 and
Sang-Hun Lee1,2,3*
Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, South Korea,1 Institute of Mental Health, College of Medicine, Hanyang University, Seoul 133-791, South Korea,2 Cell Therapy Research Center, College of Medicine, Hanyang University, Seoul 133-791, South Korea,3 Department of Anatomy, Korea University College of Medicine, Seoul 136-705, South Korea,4 Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, showa-ku, Nagoya 466-8550, Japan,5 Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0101, Japan,6 Department of Microbiology, College of Medicine, Hanyang University, Seoul 133-791, South Korea,7 Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, South Korea8
Received 6 January 2007/ Returned for modification 5 February 2007/ Accepted 28 March 2007
In the developing mouse brain, the highest Bcl-XL expression is seen at the peak of neurogenesis, whereas the peak of Bax expression coincides with the astrogenic period. While such observations suggest an active role of the Bcl-2 family proteins in the generation of neurons and astrocytes, no definitive demonstration has been provided to date. Using combinations of gain- and loss-of-function assays in vivo and in vitro, we provide evidence for instructive roles of these proteins in neuronal and astrocytic fate specification. Specifically, in Bax knockout mice, astrocyte formation was decreased in the developing cortices. Overexpression of Bcl-XL and Bax in embryonic cortical precursors induced neural and astrocytic differentiation, respectively, while inhibitory RNAs led to the opposite results. Importantly, inhibition of caspase activity, dimerization, or mitochondrial localization of Bcl-XL/Bax proteins indicated that the differentiation effects of Bcl-XL/Bax are separable from their roles in cell survival and apoptosis. Lastly, we describe activation of intracellular signaling pathways and expression of basic helix-loop-helix transcriptional factors specific for the Bcl-2 protein-mediated differentiation.
* Corresponding author. Mailing address: Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, South Korea. Phone: 82-2-2220-0625. Fax: 82-2-2294-6270. E-mail: leesh{at}hanyang.ac.kr
Published ahead of print on 16 April 2007.
Supplemental material for this article may be found at http://mcb.asm.org/.
Present address: Molecular Neurobiology Laboratory, McLean Hospital and Harvard Medical School, Belmont, MA 02478.
Molecular and Cellular Biology, June 2007, p. 4293-4305, Vol. 27, No. 12
0270-7306/07/$08.00+0 doi:10.1128/MCB.00031-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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