title: Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis.
abstract: Apoptosis is an essential step in cavitation during embryonic epithelial morphogenesis, but its mechanisms are largely unknown. In this paper, we used embryonic stem cell-differentiated embryoid bodies (EBs) as a model and found that Bnip3 (Bcl-2/adenovirus E1B 19-kD interacting protein), a BH3-only proapoptotic protein, was highly up-regulated during cavitation in a hypoxia-dependent manner. Short hairpin RNA silencing of Bnip3 inhibited apoptosis of the core cells and delayed cavitation. We show that the Bnip3 up-regulation was mediated mainly by hypoxia-inducible factor (HIF)-2. Ablation of HIF-2α or HIF-1β, the common β subunit of HIF-1 and -2, suppressed Bnip3 up-regulation and inhibited apoptosis and cavitation. We further show that apoptosis-inducing factor (AIF) cooperated with Bnip3 to promote lumen clearance. Bnip3 silencing in AIF-null EBs nearly blocked apoptosis and cavitation. Moreover, AIF also regulated Bnip3 expression through mitochondrial production of reactive oxygen species and consequent HIF-2α stabilization. These results uncover a mechanism of cavitation through hypoxia-induced apoptosis of the core cells mediated by HIFs, Bnip3, and AIF.
authors: Department of Surgery, University of Medicine and Dentistry New Jersey Robert Wood Johnson Medical School, New Brunswick, NJ 08093, USA.
authors: Yanmei
authors: Y
authors: Qi
authors: Xiaoxiang
authors: X
authors: Tian
authors: Jie
authors: J
authors: Liu
authors: Yaling
authors: Y
authors: Han
authors: Alan M
authors: AM
authors: Graham
authors: M Celeste
authors: MC
authors: Simon
authors: Josef M
authors: JM
authors: Penninger
authors: Peter
authors: P
authors: Carmeliet
authors: Shaohua
authors: S
authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000502:physiology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009024:Morphogenesis / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051033:Apoptosis Inducing Factor; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse; C508686:BNip3 protein, mouse