title: HIF1α and pancreatic β-cell development.
abstract: During early embryogenesis, the pancreas shows a paucity of blood flow, and oxygen tension, the partial pressure of oxygen (pO(2)), is low. Later, the blood flow increases as β-cell differentiation occurs. We have previously reported that pO(2) controls β-cell development in rats. Here, we checked that hypoxia inducible factor 1α (HIF1α) is essential for this control. First, we demonstrated that the effect of pO(2) on β-cell differentiation in vitro was independent of epitheliomesenchymal interactions and that neither oxidative nor energetic stress occurred. Second, the effect of pO(2) on pancreas development was shown to be conserved among species, since increasing pO(2) to 21 vs. 3% also induced β-cell differentiation in mouse (7-fold, P<0.001) and human fetal pancreas. Third, the effect of hypoxia was mediated by HIF1α, since the addition of an HIF1α inhibitor at 3% O(2) increased the number of NGN3-expressing progenitors as compared to nontreated controls (9.2-fold, P<0.001). In contrast, when we stabilized HIF1α by deleting ex vivo the gene encoding pVHL in E13.5 pancreas from Vhl floxed mice, Ngn3 expression and β-cell development decreased in such Vhl-deleted pancreas compared to controls (2.5 fold, P<0.05, and 6.6-fold, P<0.001, respectively). Taken together, these data demonstrate that HIF1α exerts a negative control over β-cell differentiation.
authors.affiliation: Institut National de Santé et de Recherche Médicale (INSERM) U845, Research Center Growth and Signalling, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Heinis
authors.forename: Andrea
authors.initials: A
authors.lastname: Soggia
authors.forename: Camille
authors.initials: C
authors.lastname: Bechetoille
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Simon
authors.forename: Carole
authors.initials: C
authors.lastname: Peyssonnaux
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.forename: Bertrand
authors.initials: B
authors.lastname: Duvillié
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000860:Hypoxia / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D018384:Oxidative Stress; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013045:Species Specificity; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; C407737:Neurog3 protein, mouse; C494469:VHL protein, mouse