First Author | Qi Y | Year | 2012 |
Journal | J Cell Biol | Volume | 198 |
Issue | 1 | Pages | 103-14 |
PubMed ID | 22753893 | Mgi Jnum | J:190758 |
Mgi Id | MGI:5449660 | Doi | 10.1083/jcb.201111063 |
Citation | Qi Y, et al. (2012) Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis. J Cell Biol 198(1):103-14 |
abstractText | 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-2alpha or HIF-1beta, the common beta 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-2alpha stabilization. These results uncover a mechanism of cavitation through hypoxia-induced apoptosis of the core cells mediated by HIFs, Bnip3, and AIF. |