Transition from totipotency to pluripotency in mice: insights into molecular mechanisms

Totipotency is the ability of a single cell to develop into a full organism and, in mammals, is strictly associated with the early stages of development following fertilization. This unlimited developmental potential becomes quickly restricted as embryonic cells transition into a pluripotent state. The loss of totipotency seems a consequence of the zygotic genome activation (ZGA), a process that determines the switch from maternal to embryonic transcription, which in mice takes place following the first cleavage. ZGA confers to the totipotent cell a transient transcriptional profile characterized by the expression of stage-specific genes and a set of transposable elements that prepares the embryo for subsequent development. The timely silencing of this transcriptional program during the exit from totipotency is required to ensure proper development. Importantly, the molecular mechanisms regulating the transition from totipotency to pluripotency have remained elusive due to the scarcity of embryonic material. However, the development of new in vitro totipotent-like models together with advances in low-input genome-wide technologies, are providing a better mechanistic understanding of how this important transition is achieved. This review summarizes the current knowledge on the molecular determinants that regulate the exit from totipotency.