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The bHLH transcription factor Hand1 is essential for placentation and cardiac morphogenesis in the developing embryo. Here we implicate Hand1 as a molecular switch that determines whether a trophoblast stem cell continues to proliferate or commits to differentiation. We identify a novel interaction of Hand1 with a protein that contains an I-mfa (inhibitor of myogenic factor) domain that anchors Hand1 in the nucleolus where it negatively regulates Hand1 activity. In the trophoblast stem-cell line Rcho-1, nucleolar sequestration of Hand1 accompanies sustained cell proliferation and renewal, whereas release of Hand1 into the nucleus leads to its activation, thus committing cells to a differentiated giant-cell fate. Site-specific phosphorylation is required for nucleolar release of Hand1, for its dimerization and biological function, and this is mediated by the non-canonical polo-like kinase Plk4 (Sak). Sak is co-expressed in Rcho-1 cells, localizes to the nucleolus during G2 and phosphorylates Hand1 as a requirement for trophoblast stem-cell commitment to a giant-cell fate. This study defines a novel cellular mechanism for regulating Hand1 that is a crucial step in the stem-cell differentiation pathway.

Original publication




Journal article


Nat Cell Biol

Publication Date





1131 - 1141


Animals, Basic Helix-Loop-Helix Transcription Factors, Blotting, Northern, Blotting, Western, Cell Differentiation, Cell Nucleolus, Cell Proliferation, Gene Expression Regulation, Developmental, Giant Cells, Green Fluorescent Proteins, Immunoprecipitation, Mice, Myogenic Regulatory Factors, NIH 3T3 Cells, Phosphorylation, Protein Binding, Protein Phosphatase 2, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells, Trophoblasts, Two-Hybrid System Techniques