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Esrrb function is required for proper primordial germ cell development in presomite stage mouse embryos.

Dev. Biol.2019 Nov 15;455(2):382-392. Epub 2019 Jul 14
Eiichi Okamura 1 , Oliver H Tam 2 , Eszter Posfai 2 , Lingyu Li 2 , Katie Cockburn 2 , Cheryl Q E Lee 2 , Jodi Garner 2 , Janet Rossant 3
Eiichi Okamura 1 , Oliver H Tam 2 , Eszter Posfai 2 , Lingyu Li 2 , Katie Cockburn 2 , Cheryl Q E Lee 2 , Jodi Garner 2 , Janet Rossant 3
+ et al

[No authors listed]

Author information
  • 1 Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan. Electronic address: okamura.eiichi@tokushima-u.ac.jp.
  • 2 Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 3 Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Electronic address: janet.rossant@sickkids.ca.

摘要


Estrogen related receptor beta (Esrrb) is an orphan nuclear receptor that is required for self-renewal and pluripotency in mouse embryonic stem (ES) cells. However, in the early post-implantation mouse embryo, Esrrb is specifically expressed in the extraembryonic ectoderm (ExE) and plays a crucial role in trophoblast development. Previous studies showed that Esrrb is also required to maintain trophoblast stem (TS) cells, the in vitro stem cell model of the early trophoblast lineage. In order to identify regulatory targets of Esrrb in vivo, we performed microarray analysis of Esrrb-null versus wild-type post-implantation ExE, and identified 30 genes down-regulated in Esrrb-mutants. Among them is Bmp4, which is produced by the ExE and known to be critical for primordial germ cell (PGC) specification in vivo. We further identified an enhancer region bound by Esrrb at the Bmp4 locus by performing Esrrb ChIP-seq and luciferase reporter assay using TS cells. Finally, we established a knockout mouse line in which the enhancer region was deleted using CRISPR/Cas9 technology. Both Esrrb-null embryos and enhancer knockout embryos expressed lower levels of Bmp4 in the ExE, and had reduced numbers of PGCs. These results suggested that Esrrb functions as an upstream factor of Bmp4 in the ExE, regulating proper PGC development in mice.