Article abstract
Nature Cell Biology 9, 1131 - 1141 (2007)
Published online: 23 September 2007 | doi:10.1038/ncb1633
Nucleolar release of Hand1 acts as a molecular switch to determine cell fate
David M. J. Martindill1, Catherine A. Risebro1, Nicola Smart1, Maria Del Mar Franco-Viseras1, Carla O. Rosario2, Carol J. Swallow2, James W. Dennis2 & Paul R. Riley1
Abstract
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.
- Molecular Medicine Unit, UCL Institute of Child Health, London, WC1N 1EH, UK.
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Correspondence to: Paul R. Riley1 e-mail: P.Riley@ich.ucl.ac.uk
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Inspiratory muscle activity during incremental exercise in obese menInternational Journal of Obesity Original Article
Requirement of the mouse I-mfa gene for placental development and skeletal patterningThe EMBO Journal Article (02 Nov 1998)
SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiationThe EMBO Journal Article (03 Feb 2003)
