TEAD4, YAP1 and WWTR1 prevent the premature onset of pluripotency prior to the 16-cell stage.

In mice, pluripotent cells are thought to derive from cells buried inside the embryo around the 16-cell stage. is the only pluripotency gene known to be expressed specifically within inside cells at this stage. To understand how pluripotency is established, we therefore investigated the mechanisms regulating the initial activation of expression. Surprisingly, expression initiated normally in the absence of both and (), highlighting differences between embryo and stem cell models of pluripotency. However, we observed precocious ectopic expression of prior to the 16-cell stage in the absence of , and Interestingly, the repression of premature expression was sensitive to LATS kinase activity, even though LATS proteins normally do not limit activity of TEAD4, YAP1 and WWTR1 during these early stages. Finally, we present evidence for direct transcriptional repression of by YAP1, WWTR1 and TEAD4 Taken together, our observations reveal that, while embryos are initially competent to express as early as the four-cell stage, transcriptional repression prevents the premature expression of , thereby restricting the pluripotency program to the stage when inside cells are first created.