Differentiation of mouse trophoblast stem cells into a specialized cell type called giant cells requires Hand1, a bHLH transcription factor. Hand1 interacts with a wider variety of other bHLH partners than do others of its class. The authors thus wondered whether it might also interact with unrelated partners that help it time giant cell differentiation. Using a yeast two-hybrid approach, they found that Hand1 bound to a nucleolar subunit of a protein called HIC.
While Hand1 hung out with HIC in the nucleolus, trophoblast cells did not differentiate. But Hand1 exited the nucleolus at the time of their differentiation to giant cells. This exit required the phosphorylation of Hand1.
The kinase that phosphorylated Hand1, called Polo-like kinase 4, is evolutionarily conserved. Phosphorylation-dependent release of transcription factors from the nucleolus may turn out to be a widespread mechanism to control their activity.