Bmi1 facilitates primitive endoderm formation by stabilizing Gata6 during early mouse development

Fabrice Lavial, Sylvain Bessonnard, Yusuke Ohnishi, Akiko Tsumura, Anil Chandrashekran, Mark A. Fenwick, Rute A. Tomaz, Hiroyuki Hosokawa, Toshinori Nakayama, Ian Chambers, Takashi Hiiragi, Claire Chazaud, Veronique Azuara

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1445-1458
Number of pages14
JournalGenes & Development
Volume26
Issue number13
DOIs
Publication statusPublished - 1 Jul 2012

Keywords

  • Bmi1
  • Nanog
  • Gata6
  • cell fate
  • early mouse embryo
  • stem cells

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