Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT
Abstract
The arylhydrocarbon-receptor nuclear translocator (ARNT) is a member of the basic-helix-loop-helix-PAS family of heterodimeric transcription factors which includes the arylhydrocarbon receptor (AHR), hypoxia-inducible factor-1alpha (HIF-1alpha) and the Drosophila single-minded protein (Sim). ARNT forms heterodimeric complexes with the arylhydrocarbon receptor, HIF-1alpha, Sim and the PAS protein Per. In response to environmental pollutants, AHR-ARNT heterodimers regulate genes involved in the metabolism of xenobiotics, whereas ARNT-HIF-1alpha heterodimers probably regulate those involved in the response to oxygen deprivation. By generating a targeted disruption of the Arnt locus in the mouse, we show here that Arnt-/- embryonic stem cells fail to activate genes that normally respond to low oxygen tension. Arnt-/- ES cells also failed to respond to a decrease in glucose concentration, indicating that ARNT is crucial in the response to hypoxia and to hypoglycaemia. Arnt-/- embryos were not viable past embryonic day 10.5 and showed defective angiogenesis of the yolk sac and branchial arches, stunted development and embryo wasting. The defect in blood vessel formation in Arnt-/- yolk sacs is similar to the angiogenic abnormalities reported for mice deficient in vascular endothelial growth factor or tissue factor. On the basis of these findings, we propose a model in which increasing tissue mass during organogenesis leads to the formation of hypoxic/nutrient-deprived cells, the su…
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One Arnt null model disrupted the bHLH domain by inserting a NeoPGK cassette; another removed the bHLH exon by homologous recombination.
“One model was developed through a gene targeting approach that created a disruption of the bHLH domain with the insertion of a NeoPGK cassette (Maltepe et al., 1997). In another, homologous recombination was used to remove the bHLH exon (Kozak et al., 1997).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Maltepe et al., 1997
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“Initial studies focused on generating Arnt null models (Kozak et al. 1997; Maltepe et al. 1997).”
BackgroundMethodSelf-citation
- Authors
- Maltepe, E., Schmidt, J. V., Baunoch, D., Bradfield, C. A., & Simon, M. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Chicago (US)
- Venue
- Nature
- Published
- 1997-03
- Volume
- 386
- Issue
- 6623
- Pages
- 403-407
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1984604224
- Cited by
- 781
- References
- 2
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 8 · 2023: 14 · 2022: 16 · 2021: 11 · 2020: 14 · 2019: 20 · 2018: 11 · 2017: 18 · 2016: 18 · 2015: 10 · 2014: 19 · 2013: 24 · 2012: 29
- FWCI
- 19.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- ARNT, hypoxia-inducible factor-1α, angiogenesis, hypoxia, glucose deprivation, hypoglycemia, yolk sac, branchial arches, embryonic lethality, vascular endothelial growth factor, tissue factor, aryl hydrocarbon receptor, embryonic stem cells, vascularization, organogenesis
- MeSH terms
- Animals, DNA-Binding Proteins, Fetal Death, Embryonic and Fetal Development, Glucose, Neovascularization, Pathologic, Oxygen, Stem Cells, Transcription Factors, Yolk Sac, Mutagenesis, Insertional, Helix-Loop-Helix Motifs, Receptors, Aryl Hydrocarbon, Gene Targeting, Gene Expression Regulation, Developmental, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator
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