Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS.
Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. Here we show that a novel HIF family basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim) protein, which is expressed predominantly during embryonic and neonatal stages and thereby designated NEPAS (neonatal and embryonic PAS), acts as a negative regulator of HIF-mediated gene expression. NEPAS mRNA is derived from the HIF-3alpha gene by alternative splicing, replacing the first exon of HIF-3alpha with that of inhibitory PAS. NEPAS can dimerize with Arnt and exhibits only low levels of transcriptional activity, similar to that of HIF-3alpha. NEPAS suppressed reporter gene expression driven by HIF-1alpha and HIF-2alpha. By generating mice with a targeted disruption of the NEPAS/HIF-3alpha locus, we found that homozygous mutant mice (NEPAS/HIF-3alpha(-)(/)(-)) were viable but displayed enlargement of the right ventricle and impaired lung remodeling. The expression of endothelin 1 and platelet-derived growth factor beta was increased in the lung endothelial cells of NEPAS/HIF-3alpha-null mice. These results demonstrate a novel regulatory mechanism in which the activities of HIF-1alpha and HIF-2alpha are negatively regulated by NEPAS in endothelial cells, which is pertinent to lung and heart development during the embryonic and neonatal stages.
Yamashita
Toshiharu
T
Department of Regenerative Medicine, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.
Ohneda
Osamu
O
Nagano
Masumi
M
Iemitsu
Motoyuki
M
Makino
Yuichi
Y
Tanaka
Hirotoshi
H
Miyauchi
Takashi
T
Goto
Katsutoshi
K
Ohneda
Kinuko
K
Fujii-Kuriyama
Yoshiaki
Y
Poellinger
Lorenz
L
Yamamoto
Masayuki
M
D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018376:Cardiovascular Abnormalities / Q000378:metabolism*; D002469:Cell Separation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006321:Heart / Q000196:embryology*; D008168:Lung / Q000002:abnormalities* / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000172:deficiency*; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D019332:Endothelin-1; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C444643:Hif3a protein, mouse