E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration

Dev Cell. 2020 Feb 10;52(3):335-349.e7. doi: 10.1016/j.devcel.2019.12.016. Epub 2020 Jan 23.


E2F transcription factors control the cytokinesis machinery and thereby ploidy in hepatocytes. If or how these proteins limit proliferation of polyploid cells with extra centrosomes remains unknown. Here, we show that the PIDDosome, a signaling platform essential for caspase-2-activation, limits hepatocyte ploidy and is instructed by the E2F network to control p53 in the developing as well as regenerating liver. Casp2 and Pidd1 act as direct transcriptional targets of E2F1 and its antagonists, E2F7 and E2F8, that together co-regulate PIDDosome expression during juvenile liver growth and regeneration. Of note, whereas hepatocyte aneuploidy correlates with the basal ploidy state, the degree of aneuploidy itself is not limited by PIDDosome-dependent p53 activation. Finally, we provide evidence that the same signaling network is engaged to control ploidy in the human liver after resection. Our study defines the PIDDosome as a primary target to manipulate hepatocyte ploidy and proliferation rates in the regenerating liver.

Keywords: PIDDosome; caspases; liver development; p53; polyploidy; regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy
  • Animals
  • CRADD Signaling Adaptor Protein / physiology
  • Caspase 2 / physiology*
  • Centrosome
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • Cytokinesis
  • Death Domain Receptor Signaling Adaptor Proteins / physiology*
  • E2F Transcription Factors / physiology*
  • Female
  • Hepatocytes / cytology*
  • Hepatocytes / metabolism
  • Humans
  • Liver Regeneration*
  • Male
  • Mice
  • Mice, Knockout
  • Polyploidy*
  • Tumor Suppressor Protein p53 / physiology*


  • CRADD Signaling Adaptor Protein
  • Cdkn1a protein, mouse
  • Cradd protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Death Domain Receptor Signaling Adaptor Proteins
  • E2F Transcription Factors
  • Pidd1 protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Casp2 protein, mouse
  • Caspase 2