Embryonic development is tightly controlled. The clustered genes of the Hox family of homeobox proteins play an important part in regulating this development and also proliferation. They specify embryonic structures along the body axis, and are associated with normal and malignant cell growth1,2,3,4. The cell-cycle regulator geminin controls replication by binding to the licensing factor Cdt1, and is involved in neural differentiation5,6,7. Here, we show that murine geminin associates transiently with members of the Hox-repressing polycomb complex, with the chromatin of Hox regulatory DNA elements and with Hox proteins. Gain- and loss-of-function experiments in the chick neural tube demonstrate that geminin modulates the anterior boundary of Hoxb9 transcription, which suggests a polycomb-like activity for geminin. The interaction between geminin and Hox proteins prevents Hox proteins from binding to DNA, inhibits Hox-dependent transcriptional activation of reporter and endogenous downstream target genes, and displaces Cdt1 from its complex with geminin. By establishing competitive regulation, geminin functions as a coordinator of developmental and proliferative control.
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We thank D. Duboule, A. Dutta, C. J. Tabin, S. Potter, R. Maas and H. Koseki for plasmids and antibodies, M. Pitulescu for discussions, J. Wittbrodt for communication and discussion of unpublished results, and P. Gruss and D. Gallwitz for their continuous support. This work was funded by the Max Planck Society and a DFG grant.
The authors declare that they have no competing financial interests.
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