Bmi1 facilitates primitive endoderm formation by stabilizing Gata6 during early mouse development
- Fabrice Lavial1,
- Sylvain Bessonnard2,
- Yusuke Ohnishi3,6,
- Akiko Tsumura3,7,
- Anil Chandrashekran1,
- Mark A. Fenwick1,
- Rute A. Tomaz1,
- Hiroyuki Hosokawa4,
- Toshinori Nakayama4,
- Ian Chambers5,
- Takashi Hiiragi3,6,
- Claire Chazaud2 and
- Véronique Azuara1,8
- 1Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom;
- 2GReD, Inserm U931/CNRS UMR6247, Clermont Université, 63001 Clermont-Ferrand Cedex, France;
- 3Max-Planck-Institut für Molekulare Biomedizin, 48149 Münster, Germany;
- 4Department of Immunology, Graduate School of Medicine, Chiba University, JST, CREST, Chiba 260-8670, Japan;
- 5Institute for Stem Cell Research, University of Edinburgh, Edinburgh EH9 3JQ, Scotland, United Kingdom
Abstract
The transcription factors Nanog and Gata6 are critical to specify the epiblast versus primitive endoderm (PrE) lineages. However, little is known about the mechanisms that regulate the protein stability and activity of these factors in the developing embryo. Here we uncover an early developmental function for the Polycomb group member Bmi1 in supporting PrE lineage formation through Gata6 protein stabilization. We show that Bmi1 is enriched in the extraembryonic (endoderm [XEN] and trophectodermal stem [TS]) compartment and repressed by Nanog in pluripotent embryonic stem (ES) cells. In vivo, Bmi1 overlaps with the nascent Gata6 and Nanog protein from the eight-cell stage onward before it preferentially cosegregates with Gata6 in PrE progenitors. Mechanistically, we demonstrate that Bmi1 interacts with Gata6 in a Ring finger-dependent manner to confer protection against Gata6 ubiquitination and proteasomal degradation. A direct role for Bmi1 in cell fate allocation is established by loss-of-function experiments in chimeric embryoid bodies. We thus propose a novel regulatory pathway by which Bmi1 action on Gata6 stability could alter the balance between Gata6 and Nanog protein levels to introduce a bias toward a PrE identity in a cell-autonomous manner.
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Footnotes
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↵8 Corresponding author
E-mail v.azuara{at}imperial.ac.uk
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.188193.112.
- Received January 31, 2012.
- Accepted May 17, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press