Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident

In order to maintain a stable karyotype, the eukaryotic cell cycle is coord inated such that only one round of S phase precedes each mitosis, and mitos is is not initiated until DNA replication is completed. Several checkpoints and regulatory proteins have been defined in lower eukaryotes that govern this coordination, but little is known about the proteins that are involved in mammalian cells. Previously, we have shown that the winged-helix transc ription factor Trident - also known as HFH-11, FKL16 and WIN [1-3] - is exc lusively expressed in cycling cells and is phosphorylated during mitosis [1 ,4]. The cellular function of Trident has yet to be described, however, Her e, we have shown that disruption of the Trident gene in mice resulted in po stnatal death, most probably because of circulatory failure. Histological a nalysis of Trident(-/-) embryos from embryonic day 10 (E10) onwards reveale d a specific, characteristic defect in the developing myocardium, The orien tation of the myocytes was highly irregular and the nuclei of these disorga nized cardiomyocytes were clearly polyploid with up to a 50-fold increase i n DNA content. Polyploidy was also observed in embryonic hepatocytes. Our r esults indicate that expression of Trident is required to prevent multiple rounds of S phase in the heart and the liver. Trident therefore appears to have a role in preventing DNA re-replication during the G2 and M phases. (C ) Current Biology Ltd ISSN 0960-9822.