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

Sladky, V. C., Knapp, K., Soratroi, C., Heppke, J., Eichin, F., Rocamora-Reverte, L., Szabo, T. G., Bongiovanni, L., Westendorp, B., Moreno, E., van Liere, E. A., Bakker, B., Spierings, D. C. J., Wardenaar, R., Pereyra, D., Starlinger, P., Schultze, S., Trauner, M., Stojakovic, T., Scharnagl, H., Fava, L. L., Foijer, F., de Bruin, A. & Villunger, A., 13-Jan-2020, In : Developmental Cell.

Research output: Contribution to journalArticleAcademicpeer-review

  • Valentina C Sladky
  • Katja Knapp
  • Claudia Soratroi
  • Julia Heppke
  • Felix Eichin
  • Lourdes Rocamora-Reverte
  • Tamas G Szabo
  • Laura Bongiovanni
  • Bart Westendorp
  • Eva Moreno
  • Elsbeth A van Liere
  • Bjorn Bakker
  • Diana C J Spierings
  • René Wardenaar
  • David Pereyra
  • Patrick Starlinger
  • Simon Schultze
  • Michael Trauner
  • Tatjana Stojakovic
  • Hubert Scharnagl
  • Luca L Fava
  • Floris Foijer
  • Alain de Bruin
  • Andreas Villunger

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.

Original languageEnglish
JournalDevelopmental Cell
Publication statusE-pub ahead of print - 13-Jan-2020

ID: 113116848