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Molecular and Cellular Biology, October 2003, p. 6739-6749, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6739-6749.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Defective Brain Development in Mice Lacking the Hif-1{alpha} Gene in Neural Cells

Shuhei Tomita,1,2,3,4* Masaki Ueno,5 Masami Sakamoto,6 Yuki Kitahama,1 Masaaki Ueki,7 Nobuhiro Maekawa,7 Haruhiko Sakamoto,5 Max Gassmann,8 Ryoichiro Kageyama,6 Natsuo Ueda,3 Frank J. Gonzalez,4 and Yousuke Takahama1,2

Department of Immune System Development, RIKEN Research Center for Allergy and Immunology,1 Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Kuramoto, Tokushima 770-8503,2 Departments of Biochemistry,3 Pathology and Host Defense,5 Anesthesiology and Emergency Medicine, Kagawa Medical University, Miki, Kagawa 761-0793,7 Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan,6 Institute of Veterinary Physiology, University of Zürich, CH-8057 Zürich, Switzerland,8 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208924

Received 30 December 2002/ Returned for modification 20 March 2003/ Accepted 16 June 2003

Hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) is essential for vascular development during embryogenesis and pathogenesis. However, little is known about its role in brain development. To investigate the function of HIF-1{alpha} in the central nervous system, a conditional knockout mouse was made with the Cre/LoxP system with a nestin promoter-driven Cre. Neural cell-specific HIF-1{alpha}-deficient mice exhibit hydrocephalus accompanied by a reduction in neural cells and an impairment of spatial memory. Apoptosis of neural cells coincided with vascular regression in the telencephalon of mutant embryos, and these embryonic defects were successfully restored by in vivo gene delivery of HIF-1{alpha} to the embryos. These results showed that expression of HIF-1{alpha} in neural cells was essential for normal development of the brain and established a mouse model that would be useful for the evaluation of therapeutic strategies for ischemia, including hypoxia-mediated hydrocephalus.

* Corresponding author. Mailing address: Department of Immune System Development, RIKEN Research Center for Allergy and Immunology, and Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Kuramoto, Tokushima 770-8503, Japan. Phone: 81 88 633 9472. Fax: 81 88 633 9473. E-mail: tomita{at}genome.tokushima-u.ac.jp.

Molecular and Cellular Biology, October 2003, p. 6739-6749, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6739-6749.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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