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PMID: 12972594 Published · ppublish English Journal Article

Defective brain development in mice lacking the Hif-1alpha gene in neural cells.

Molecular and cellular biology ·Vol. 23 ·No. 19 ·2003-10-00 ·Pages 6739-49

Tomita S, Ueno M, Sakamoto M, Kitahama Y, Ueki M, Maekawa N, Sakamoto H, Gassmann M, Kageyama R, Ueda N, Gonzalez FJ, Takahama Y

Abstract

Hypoxia-inducible factor 1alpha (HIF-1alpha) 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-1alpha 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-1alpha-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-1alpha to the embryos. These results showed that expression of HIF-1alpha 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.

MeSH Terms
Animals Animals, Genetically Modified Apoptosis/genetics Behavior, Animal Brain/blood supply,embryology,pathology Cell Hypoxia/genetics Cells, Cultured DNA-Binding Proteins/genetics,physiology Endothelial Growth Factors/metabolism Fibroblasts/metabolism,ultrastructure Gene Deletion Gene Expression Regulation, Developmental Glucose Transporter Type 1 Hydrocephalus/embryology,pathology Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Intercellular Signaling Peptides and Proteins/metabolism Lymphokines/metabolism Mice Mice, Knockout Monosaccharide Transport Proteins/metabolism Neurons/physiology,ultrastructure Nuclear Proteins/genetics,physiology Transcription Factors Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Chemicals
DNA-Binding Proteins Endothelial Growth Factors Glucose Transporter Type 1 Hif1a protein, mouse Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Intercellular Signaling Peptides and Proteins Lymphokines Monosaccharide Transport Proteins Nuclear Proteins Transcription Factors Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Tomita Shuhei
Department of Immune System Development, RIKEN Research Center for Allergy and Immunology, Tokushima 770-8503, Japan. tomita@genome.tokushima-u.ac.jp
Ueno Masaki
Sakamoto Masami
Kitahama Yuki
Ueki Masaaki
Maekawa Nobuhiro
Sakamoto Haruhiko
Gassmann Max
Kageyama Ryoichiro
Ueda Natsuo
Gonzalez Frank J
Takahama Yousuke
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.19.6739-6749.2003
Email
tomita@genome.tokushima-u.ac.jp
Published
2003-10-00
Pages
6739-49
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC193947
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.23.19.6739-6749.2003 PMC Full Text View journal details
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