The preimplantation embryo is the source of embryonic stem (ES) cells, and therefore provides a unique sys- tem in which to understand the establishment of pluripotency. The transcription factors Oct4 (Pou5f1) and Sox2 are necessary for pluripotency in ES cells and are key regulators of induced pluripotency. Our evidence indicates that in the mouse embryo, Oct4 and Sox2 have an additional role: promoting differentiation of the primitive endoderm (PE), an essential extraembryonic tissue. Our data support a model wherein Sox2 regulates PE genes non cell-autonomously, and Oct4 regulates PE genes cell-autonomously. The gene targets of Oct4 and Sox2 have been described in the stem cell context, but the gene targets of Oct4 and Sox2 in the embryo are unknown. The objectives of this study are to resolve the mechanisms by which Oct4 and Sox2 regulate PE cell fate in the embryo, to identify the targets of Oct4 and Sox2 in the embryo and in PE cells, and to discover how Oct4 is regulated to induce pluripotency genes in some cells, and PE genes in other cells of the embryo. To achieve these goals, we will integrate classical embryological and modern genomic approaches. This study is expected to impact stem cell research, because understanding how to regulate dual roles of Oct4 in promoting pluripotency and PE differentiation will reveal new ways to selectively promote or prevent PE differentiation in stem cells and during reprogramming. This study is expected to impact fertility research be- cause we will identify new regulators of extraembryonic tissues, which are essential for establishment of pregnancy and healthy fetal development.
In stem cells, Oct4 and Sox2 are two factors that promote pluripotency and repress of differentiation, but our studies in the mouse embryo show that Oct4 and Sox2 play an unexpected role, promoting differentiation of an extraembryonic tissue that is essential for embryo survival. We aim to discover how Oct4 and Sox2 balance these two opposing roles, protecting pluripotency in some cells, and promoting differentiation in others. Our research will impact stem cell biology, where balancing pluripotency and differentiation is essential for making and using stem cells for clinical applications, and reproductive biology, where identification of new regulators of embryogenesis could improve genetic diagnosis of recurrent pregnancy loss.
|Ralston, Amy (2016) Investigations at the 'Four-Front' of Mammalian Development. Trends Genet 32:457-8|
|Parenti, Anthony; Halbisen, Michael A; Wang, Kai et al. (2016) OSKM Induce Extraembryonic Endoderm Stem Cells in Parallel to Induced Pluripotent Stem Cells. Stem Cell Reports 6:447-55|
|Parenti, Anthony; Ralston, Amy (2015) Three, two, oneâ€¦ TROPHO-BLAST OFF! Cell Stem Cell 17:499-500|
|Blij, Stephanie; Parenti, Anthony; Tabatabai-Yazdi, Neeloufar et al. (2015) Cdx2 efficiently induces trophoblast stem-like cells in naÃ¯ve, but not primed, pluripotent stem cells. Stem Cells Dev 24:1352-65|
|Frum, Tristan; Ralston, Amy (2015) Cell signaling and transcription factors regulating cell fate during formation of the mouse blastocyst. Trends Genet 31:402-10|
|Halbisen, Michael A; Ralston, Amy (2014) Have you seen? Shaking up the salt and pepper: origins of cellular heterogeneity in the inner cell mass of the blastocyst. EMBO J 33:280-1|
|Wicklow, Eryn; Blij, Stephanie; Frum, Tristan et al. (2014) HIPPO pathway members restrict SOX2 to the inner cell mass where it promotes ICM fates in the mouse blastocyst. PLoS Genet 10:e1004618|
|Frum, Tristan; Halbisen, Michael A; Wang, Chaoyang et al. (2013) Oct4 cell-autonomously promotes primitive endoderm development in the mouse blastocyst. Dev Cell 25:610-22|