The molecular mechanisms that regulate the transition from totipotency into divergent cellular states are unclear. Two new studies show that the transcription factors TFAP2C, NR5A2 and TEAD4 (TNT) support the formation of a transient bipotent state by activating early pluripotency and trophectoderm genes and modulating HIPPO signaling.
In mammals, life begins as a totipotent embryo that has the capacity to give rise to hundreds of different cell types in the organism. This remarkable ability is acquired at conception and is rapidly lost within a few cell divisions. Totipotency naturally occurs in the early stages of preimplantation embryo development. In mice, totipotency is thought to be established around the 1- to 2-cell stage when the embryo undergoes zygotic gene activation (ZGA)1. By the time the embryo reaches the 8-cell stage and undergoes compaction and polarization, totipotency is already lost. At the 16- to 32-cell stage (morula), the outer and inner cells begin to acquire multipotent and pluripotent cellular states to facilitate the formation of the future trophectoderm (TE) and inner cell mass (ICM) lineages in blastocysts, respectively (Fig. 1).