Defective brain development in mice lacking the Hif-1alpha gene in neural cells.
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.
Tomita
Shuhei
S
Department of Immune System Development, RIKEN Research Center for Allergy and Immunology, Tokushima 770-8503, Japan. tomita@genome.tokushima-u.ac.jp
Ueno
Masaki
M
Sakamoto
Masami
M
Kitahama
Yuki
Y
Ueki
Masaaki
M
Maekawa
Nobuhiro
N
Sakamoto
Haruhiko
H
Gassmann
Max
M
Kageyama
Ryoichiro
R
Ueda
Natsuo
N
Gonzalez
Frank J
FJ
Takahama
Yousuke
Y
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D001522:Behavior, Animal; D001921:Brain / Q000098:blood supply / Q000196:embryology* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051272:Glucose Transporter Type 1; D006849:Hydrocephalus / Q000196:embryology / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors