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Title: Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis
Authors: Qi, Yanmei ×
Tian, Xiaoxiang
Liu, Jie
Graham, Alan M
Simon, M Celeste
Penninger, Josef M
Carmeliet, Peter #
Issue Date: Jul-2012
Publisher: Rockefeller Institute Press
Series Title: Journal of Cell Biology vol:198 issue:1 pages:103-114
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.
ISSN: 0021-9525
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Angiogenesis and Neurovascular Link (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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