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

• Published in: Developmental cell Vol. 52; no. 3; pp. 335 - 349.e7
• Main Authors: Sladky, Valentina C., Knapp, Katja, Soratroi, Claudia, Heppke, Julia, Eichin, Felix, Rocamora-Reverte, Lourdes, Szabo, Tamas G., Bongiovanni, Laura, Westendorp, Bart, Moreno, Eva, van Liere, Elsbeth A., Bakker, Bjorn, Spierings, Diana C.J., Wardenaar, René, Pereyra, David, Starlinger, Patrick, Schultze, Simon, Trauner, Michael, Stojakovic, Tatjana, Scharnagl, Hubert, Fava, Luca L., Foijer, Floris, de Bruin, Alain, Villunger, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2020
• Subjects: caspases; liver development; p53; PIDDosome; polyploidy; regeneration; PIDDosome; liver development; polyploidy; regeneration; caspases; p53
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.12.016

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. [Display omitted] •The PIDDosome controls hepatocyte ploidy during postnatal development & regeneration•The PIDDosome defines the speed of liver regeneration posthepatectomy•Aneuploidy in the liver correlates with basal ploidy state but is not limited by CASP2•E2F family members regulate expression of CASP2 and PIDD1 for liver ploidy control Sladky et al. report a key role for the PIDDosome in regulating p53 activation to limit hepatocyte polyploidy during juvenile liver growth and regeneration. Expression of essential PIDDosome components is controlled by a E2F-family regulated circuitry. The study defines the PIDDosome as a putative target to enhance liver regeneration.