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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM104009-04
Application #
9126573
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2013-09-01
Project End
2019-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Michigan State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Ralston, Amy (2018) XEN and the Art of Stem Cell Maintenance: Molecular Mechanisms Maintaining Cell Fate and Self-Renewal in Extraembryonic Endoderm Stem (XEN) Cell Lines. Adv Anat Embryol Cell Biol 229:69-78
Midic, Uros; Vincent, Kailey A; Wang, Kai et al. (2018) Novel key roles for structural maintenance of chromosome flexible domain containing 1 (Smchd1) during preimplantation mouse development. Mol Reprod Dev 85:635-648
Watts, Jennifer; Lokken, Alyson; Moauro, Alexandra et al. (2018) Capturing and Interconverting Embryonic Cell Fates in a Dish. Curr Top Dev Biol 128:181-202
Frum, Tristan; Ralston, Amy (2018) AttrActin' Attention to Early Mouse Development. Cell 173:544-545
Aykul, Senem; Parenti, Anthony; Chu, Kit Yee et al. (2017) Biochemical and Cellular Analysis Reveals Ligand Binding Specificities, a Molecular Basis for Ligand Recognition, and Membrane Association-dependent Activities of Cripto-1 and Cryptic. J Biol Chem 292:4138-4151
Huang, Daosheng; Guo, Guoji; Yuan, Ping et al. (2017) The role of Cdx2 as a lineage specific transcriptional repressor for pluripotent network during the first developmental cell lineage segregation. Sci Rep 7:17156
Ralston, Amy (2016) Investigations at the 'Four-Front' of Mammalian Development. Trends Genet 32:457-458
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 6:447-455
Frum, Tristan; Ralston, Amy (2015) Cell signaling and transcription factors regulating cell fate during formation of the mouse blastocyst. Trends Genet 31:402-10
Parenti, Anthony; Ralston, Amy (2015) Three, two, oneā€¦ TROPHO-BLAST OFF! Cell Stem Cell 17:499-500

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