| First Author | Martindill DM | Year | 2007 |
| Journal | Nat Cell Biol | Volume | 9 |
| Issue | 10 | Pages | 1131-41 |
| PubMed ID | 17891141 | Mgi Jnum | J:152657 |
| Mgi Id | MGI:4359361 | Doi | 10.1038/ncb1633 |
| Citation | Martindill DM, et al. (2007) Nucleolar release of Hand1 acts as a molecular switch to determine cell fate. Nat Cell Biol 9(10):1131-41 |
| abstractText | 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. |
