Multipotent cell lineages in early mouse development depend on SOX2 function

Abstract

Each cell lineage specified in the preimplantation mammalian embryo depends on intrinsic factors for its development, but there is also mutual interdependence between them. OCT4 is required for the ICM/epiblast lineage, and at transient high levels for extraembryonic endoderm, but also indirectly through its role in regulating Fgf4 expression, for the establishment and proliferation of extraembryonic ectoderm from polar trophectoderm. The transcription factor SOX2 has also been implicated in the regulation of Fgf4 expression. We have used gene targeting to inactivate Sox2, examining the phenotypic consequences in mutant embryos and in chimeras in which the epiblast is rescued with wild-type ES cells. We find a cell-autonomous requirement for the gene in both epiblast and extraembryonic ectoderm, the multipotent precursors of all embryonic and trophoblast cell types, respectively. However, an earlier role within the ICM may be masked by the persistence of maternal protein, whereas the lack of SOX2 only becomes critical in the chorion after 7.5 days postcoitum. Our data suggest that maternal components could be involved in establishing early cell fate decisions and that a combinatorial code, requiring SOX2 and OCT4, specifies the first three lineages present at implantation. Early embryonic development in mammals is characterized by a series of cell fate decisions that restrict developmental potential in an asymmetric fashion. There is, however, no evidence that this is caused by differential allocation of maternal cytoplasmic determinants as in many other animals. Although the fertilized egg may have a polarity that can predict the definitive axes of the later postimplantation embryo, this at best confers a bias to what is a very regulative system. Cell position seems more important. Thus, the first restriction of developmental potential to the trophectoderm lineage occurs in blastomeres located on the outside of the morula, whereas inside cells become inner cell mass (ICM). Subsequently, the ICM is specified into two lineages, embryonic ectoderm (epiblast), which gives rise to all cell types of the embryo as well as to extraembryonic mesoderm, and extraembryonic (primitive) endoderm, which is found on the surface of the ICM adjacent to the blastocoel cavity and contributes to the yolk sac (Lu et al. 2001).There is a dependence on each of these three early distinct lineages for the survival, patterning, and differentiation of each of the others during subsequent development postimplantation. The polar trophectoderm receives signals from the underlying ICM, triggering its proliferation and differentiation into extraembryonic ectoderm (ExE). This continues to proliferate and gives rise to the various trophoblast cell types of the placenta and to structures such as the chorion. Conversely, the mural trophectoderm, which is not in contact with the ICM, ceases to divide and terminally differentiates into primary trophoblast giant cells (Rossant and Cross 2001). The primitive endoderm also forms two distinct cell types...

Ube2s regulates Sox2 stability and mouse ES cell maintenance

“…16 Of note, Sox2 is highly expressed in the neurogenetic tissues, such as the hippocampus and central canal, and has a critical role in unperturbed neurogenesis. [17][18][19] These insights corroborate our interest in exploring the role of K11-linked polyubiquitin chain assembly machineries in fine-tuning the precise level of Sox2 in mES cells.…”

“…17,37 However, the function of Sox2 is not restricted to ES cells. Rather, it is involved in a variety of fetal and adult stem cells, such as neural stem cells, retina and pituitary progenitor cells.…”

“…Interestingly, the importance of the interaction extends to the role of Ube2s in regulating ES cell differentiation to the neural ectoderm lineage. As Sox2 is important for neurogenesis in the adult central nerve system through its maintenance of neural stem and progenitor cells, [17][18][19] as a regulator of Sox2 ubiquitination, Ube2s may have yet unexplored role in regulating neurogenesis, and its dysfunction may be related to neurodegenerative diseases.…”

Sox2 is dispensable for primary melanoma and metastasis formation

“…The transcription factor Sox2 plays a crucial role during embryogenesis and is necessary for proper development of multiple cell types 1,2 . It controls pluripotency in embryonic stem cells and is one of the four originally described factors required for reprogramming of differentiated cells into induced pluripotent stem cells 3,4 .…”

SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer

“…12 SOX2 is expressed during early embryogenesis and has an important role in embryonic and extra-embryonic cell types. 13 In detail, SOX2 is believed to inhibit neurogenesis and to preserve cellular proliferative potential during development of the central nervous system. 14 Furthermore, SOX2 is a key regulator of foregut development.…”