Cell cycle switch to endocycle: the nucleolus lends a hand.

The bHLH transcription factor Hand1 is essential for placentation and cardiac morphogenesis but how its developmental activity is regulated is largely unknown. We recently showed that Hand1 is sequestered in the nucleoli of rodent trophoblast stem (TS) cells by the I-mfa domain-containing protein HICp40 and that this is associated with their proliferation and continuing self-renewal. However when these cells commit to differentiate into trophoblast giant (TG) cells, Hand1 is phosphorylated by the polo-like kinase Plk4 (Sak) and released into the nucleus to activate downstream target genes. This event underlies the release of Hand1 from the nucleolus and represents the 'molecular switch' that promotes mitotic cell cycle exit and the onset of endoreduplication. In this brief discussion we examine the wider implications of these findings and address some of the unanswered questions that remain.