Wnt Signaling Regulates Hepatocyte Cell Division by a Transcriptional Repressor Cascade

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a new mechanism of cell division control in the postnatal liver, in which Wnt/ßcatenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. Tbx3 directly represses transcription of E2F7 and E2F8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a new paradigm for exploring how commonly active developmental signals impact cell cycle completion. Overall design: Primary mouse hepatocytes that were overexpressing HA-tagged TBX3 protein were used for each chromatin IP reaction. Anti-HA antibody was used for chromatin immunoprecipitation (ChIP). Two biological replicates were generated for Input and ChIP DNA.